U.S. patent number 7,238,684 [Application Number 10/511,984] was granted by the patent office on 2007-07-03 for benzothiadiazepine derivatives, processes for their preparation and pharmaceutical compositions containing them.
This patent grant is currently assigned to AstraZeneca AB. Invention is credited to Suzanne Alenfalk, Stig Jonas Bostrom, Mikael Ulf Johan Dahlstrom, Mats Peter Nordberg, Ingemar Starke, Andreas Christer Wallberg.
United States Patent |
7,238,684 |
Starke , et al. |
July 3, 2007 |
Benzothiadiazepine derivatives, processes for their preparation and
pharmaceutical compositions containing them
Abstract
The present invention relates to compounds of formula (I):
wherein R.sup.v, R.sup.1, R.sup.2, R.sup.x, R.sup.y, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.z and v are as defined within;
pharmaceutically acceptable salts, solvates, solvates or such salts
and prodrugs thereof and their use as ileal bile acid transport
(IBAT) inhibitors for the treatment of hyperlipidaemia. Processes
for their manufacture and pharmaceutical compositions containing
them are also described.
Inventors: |
Starke; Ingemar (Molndal,
SE), Dahlstrom; Mikael Ulf Johan (Molndal,
SE), Nordberg; Mats Peter (Molndal, SE),
Alenfalk; Suzanne (Molndal, SE), Wallberg; Andreas
Christer (Molndal, SE), Bostrom; Stig Jonas
(Molndal, SE) |
Assignee: |
AstraZeneca AB (Sodertalje,
SE)
|
Family
ID: |
9935492 |
Appl.
No.: |
10/511,984 |
Filed: |
April 23, 2003 |
PCT
Filed: |
April 23, 2003 |
PCT No.: |
PCT/GB03/01742 |
371(c)(1),(2),(4) Date: |
October 21, 2004 |
PCT
Pub. No.: |
WO03/091232 |
PCT
Pub. Date: |
November 06, 2003 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20050143368 A1 |
Jun 30, 2005 |
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Foreign Application Priority Data
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Apr 25, 2002 [GB] |
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0209467.0 |
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Current U.S.
Class: |
514/211.08;
540/545 |
Current CPC
Class: |
A61P
7/02 (20180101); A61P 3/06 (20180101); A61P
3/08 (20180101); A61P 9/00 (20180101); A61P
9/14 (20180101); A61P 29/00 (20180101); A61P
9/06 (20180101); A61P 9/04 (20180101); C07D
285/36 (20130101); A61P 1/12 (20180101); A61P
9/10 (20180101); A61P 31/00 (20180101); A61P
41/00 (20180101); A61P 43/00 (20180101) |
Current International
Class: |
C07D
285/36 (20060101); A61K 31/554 (20060101) |
Field of
Search: |
;540/545
;514/211.08 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
19825804 |
|
Dec 1999 |
|
DE |
|
0372542 |
|
Jun 1990 |
|
EP |
|
0 864 582 |
|
Sep 1998 |
|
EP |
|
2262888 |
|
Jul 1993 |
|
GB |
|
WO 93/16055 |
|
Aug 1993 |
|
WO |
|
WO 94/18183 |
|
Aug 1994 |
|
WO |
|
WO 94/18184 |
|
Aug 1994 |
|
WO |
|
WO 96/05188 |
|
Feb 1996 |
|
WO |
|
WO 96/08484 |
|
Mar 1996 |
|
WO |
|
WO 96/16051 |
|
May 1996 |
|
WO |
|
WO 97/33882 |
|
Sep 1997 |
|
WO |
|
98/38182 |
|
Sep 1998 |
|
WO |
|
WO 98/40375 |
|
Sep 1998 |
|
WO |
|
WO 99/01149 |
|
Jan 1999 |
|
WO |
|
WO 99/32478 |
|
Jul 1999 |
|
WO |
|
WO 99/35135 |
|
Jul 1999 |
|
WO |
|
WO 99/64409 |
|
Dec 1999 |
|
WO |
|
WO 99/64410 |
|
Dec 1999 |
|
WO |
|
WO 00/01687 |
|
Jan 2000 |
|
WO |
|
WO 00/38725 |
|
Jul 2000 |
|
WO |
|
WO 00/38726 |
|
Jul 2000 |
|
WO |
|
WO 00/38727 |
|
Jul 2000 |
|
WO |
|
WO 00/38728 |
|
Jul 2000 |
|
WO |
|
WO 00/38729 |
|
Jul 2000 |
|
WO |
|
WO 00/47568 |
|
Aug 2000 |
|
WO |
|
WO 00/61568 |
|
Oct 2000 |
|
WO |
|
WO 00/62810 |
|
Oct 2000 |
|
WO |
|
WO 01/60807 |
|
Aug 2001 |
|
WO |
|
01/66533 |
|
Sep 2001 |
|
WO |
|
WO 01/66533 |
|
Sep 2001 |
|
WO |
|
WO 01/68096 |
|
Sep 2001 |
|
WO |
|
WO 01/68637 |
|
Sep 2001 |
|
WO |
|
WO 02/08211 |
|
Jan 2002 |
|
WO |
|
WO 02/32428 |
|
Apr 2002 |
|
WO |
|
02/50051 |
|
Jun 2002 |
|
WO |
|
WO 02/50051 |
|
Jun 2002 |
|
WO |
|
WO 02/053548 |
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Jul 2002 |
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WO |
|
03/022286 |
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Mar 2003 |
|
WO |
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WO 03/020710 |
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Mar 2003 |
|
WO |
|
WO 03/022286 |
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Mar 2003 |
|
WO |
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WO 03/022825 |
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Mar 2003 |
|
WO |
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WO 03/022830 |
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Mar 2003 |
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WO |
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WO 03/051821 |
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Jun 2003 |
|
WO |
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WO 03/051822 |
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Jun 2003 |
|
WO |
|
WO 03/061663 |
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Jul 2003 |
|
WO |
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WO 03/106482 |
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Dec 2003 |
|
WO |
|
WO 2004/006899 |
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Jan 2004 |
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WO |
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WO 2004/076430 |
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Sep 2004 |
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WO |
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WO 2004/089350 |
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Oct 2004 |
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WO |
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Other References
Govers et al., (1994) "Characterization of the adsorption of
conjugated and unconjugated bile acids to insoluble, amorphous
calcium phosphate" Journal of Lipid Research, 35(5): 741-748. cited
by other .
Higaki et al., (1998) "Inhibition of Ileal Na.sup.+/Bile Acid
Cotransporter by S-8921 Reduces Serum Cholesterol and Prevents
Atherosclerosis in Rabbits" Ateriosclerosis, Thrombosis, and
Vascular Biology 18(8): 1304-1311. cited by other .
Ishibashi et al., (1993) "Hypercholesterolemia in low density
lipoprotein receptor knockout mice and its reversal by
adenovirus-mediated gene delivery" Journal of Clinical
Investigation 92(2): 883-893. cited by other .
Lewis et al., (1995) "Effects of 2164U90 on ileal bile acid
absorption and serum cholesterol in rats and mice" Journal of Lipid
Research, 36(5): 1098-1105. cited by other .
Plump et al., (1992) "Severe hypercholesterolemia and
atherosclerosis in apolipoprotein E-deficient mice created by
homologous recombination in ES cells" Cell 71(2):343-353. cited by
other .
Schiller (2001) "The therapy of constipation" Alimentary
Pharmacology and Therapeutics 15(6): 749-763. cited by other .
Sprong et al., (2002) "Dietary Calcium Phosphate Promotes Listeria
monocytogenes Colonization and Translocation in Rats Fed Diets
Containing Corn Oil but Not Milk Fat" J. Nutrition (US) 132(6):
1269-1274. cited by other .
Van Tilburg et al., (1989) "Na+-dependent bile acid transport in
the ileum: The balance between diarrhea and constipation"
Gastroenterology 98(1): 25-32. cited by other .
Welberg et al., (1991) "Calcium and the prevention of colon cancer"
Scandinavian J. Gastroenterology Suppl Norway 188: 52-59. cited by
other.
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Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Morgan Lewis & Bockius LLP
Claims
What claimed is:
1. A compound of formula (I): ##STR00024## wherein: R.sup.v is
selected from hydrogen or C.sub.1-6alkyl; One of R.sup.1 and
R.sup.2 are selected from hydrogen or C.sub.1-6alkyl and the other
is selected from C.sub.1-6alkyl; R.sup.x and R.sup.y are
independently selected from hydrogen, hydroxy, amino, mercapto,
C.sub.1-6alkyl, C.sub.1-6alkoxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylS(O).sub.a wherein
a is 0 to 2; R.sup.z is selected from halo, nitr, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6-alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; v is 0 5; one of R.sup.4 and
R.sup.5 is a group of formula (IA): ##STR00025## R.sup.3 and
R.sup.6 and the other of R.sup.4 and R.sup.5 are independently
selected from hydrogen, halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; wherein R.sup.3 and R.sup.6
and the other of R.sup.4 and R.sup.5 may be optionally substituted
on carbon by one or more R.sup.17; X is --O--, --N(R.sup.a)--,
--S(O).sub.b-- or --CH(R.sup.a)--; wherein R.sup.a is hydrogen or
C.sub.1-6alkyl and b is 0 2; Ring A is aryl or heteroaryl; wherein
Ring A is optionally substituted on carbon by one or more
substituents selected from R.sup.18; R.sup.7 is hydrogen,
C.sub.1-6alkyl, carbocyclyl or heterocyclyl; wherein R.sup.7 is
optionally substituted on carbon by one or more substituents
selected from R.sup.19; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.20; R.sup.8 is hydrogen or
C.sub.1-6-alkyl; R.sup.9 is hydrogen or C.sub.1-6alkyl; R.sup.10 is
hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,
sulphamoyl, hydroxyaminocarbonyl, C.sub.1-10alkyl,
C.sub.2-10alkynyl, C.sub.2-10alkynyl, C.sub.1-10alkoxy,
C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.21--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.22--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.10 is optionally substituted on carbon by
one or more substituents selected from R.sup.23; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.24; or
R.sup.10 is a group of formula (IB): ##STR00026## wherein: R.sup.11
is hydrogen or C.sub.1-6-alkyl; R.sup.12 and R.sup.13 are
independently selected from hydrogen, halo, carbamoyl, sulphamoyl,
C.sub.1-10alkyl, C.sub.2-10alkynyl, C.sub.2-10alkynyl,
C.sub.1-10alkanoyl, N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl or
heterocyclyl; wherein R.sup.12 and R.sup.13 may be independently
optionally substituted on carbon by one or more substituents
selected from R.sup.25; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.26; R.sup.14 is selected from hydrogen,
halo, carbamoyl, sulphamoyl, hydroxyaminocarbonyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.27--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.28--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.14 may be optionally substituted on
carbon by one or more substituents selected from R.sup.29; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.30; or R.sup.14 is a group of formula (IC): ##STR00027##
R.sup.15 is hydrogen or C.sub.1-6alkyl; and R.sup.16 is hydrogen or
C.sub.1-6alkyl; wherein R.sup.16 may be optionally substituted on
carbon by one or more groups selected from R.sup.31; or R.sup.15
and R.sup.16 together with the nitrogen to which they are attached
form a heterocyclyl; wherein said heterocyclyl may be optionally
substituted on carbon by one or more R.sup.37; and wherein if said
heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.38; n is 1 3;
wherein the values of R.sup.7 may be the same or different;
R.sup.17, R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29,
R.sup.31 and R.sup.37 are independently selected from halo, nitro,
cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, N--(C.sub.1-10alkyl)amino,
N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.32--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.33--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.17, R.sup.18, R.sup.19, R.sup.23,
R.sup.25, R.sup.29, R.sup.31 and R.sup.37 may be independently
optionally substituted on carbon by one or more R.sup.34; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.35; R.sup.21, R.sup.22, R.sup.27, R.sup.28, R.sup.32 or
R.sup.33 are independently selected from --O--, --NR.sup.36--,
--S(O).sub.x--, --NR.sup.36C(O)NR.sup.36--,
--NR.sup.36C(S)NR.sup.36--, --OC(O)N.dbd.C--, --NR.sup.36C(O)-- or
--C(O)NR.sup.36--; wherein R.sup.36 is selected from hydrogen or
C.sub.1-6alkyl, and x is 0 2; p, q, r and s are independently
selected from 0 2; R.sup.34 is selected from halo, hydroxy, cyano,
carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,
trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,
vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino,
acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino
and N,N-dimethylsulphamoylamino; R.sup.20, R.sup.24, R.sup.26,
R.sup.30, R.sup.35 and R.sup.38 are independently selected from
C.sub.1-6alkyl, C.sub.1-6alkanoyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; and wherein a "heteroaryl" is a totally
unsaturated, mono or bicyclic ring containing 3 12 atoms of which
at least one atom is chosen from nitrogen, sulphur and oxygen,
which heteroaryl may, unless otherwise specified, be carbon or
nitrogen linked; wherein a "heterocyclyl" is a saturated, partially
saturated or unsaturated, mono or bicyclic ring containing 3 12
atoms of which at least one atom is chosen from nitrogen, sulphur
and oxygen, which heterocyclyl may, unless otherwise specified, be
carbon or nitrogen linked, wherein a --CH2- group can optionally be
replaced by a --C(O)-- group, and a ring sulphur atom may be
optionally oxidised to form an S-oxide; and wherein a "carbocyclyl"
is a saturated, partially saturated or unsaturated, mono or
bicyclic carbon ring that contains 3 12 atoms; wherein a --CH2-
group can optionally be replaced by a --C(O) group; or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide formed on an available carboxy or hydroxy group thereof.
2. A compound of formula (I) as claimed in claim 1 wherein R.sup.v
is hydrogen or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide formed on an available carboxy or
hydroxy group thereof.
3. A compound of formula (I) as claimed in claim 1 wherein R.sup.1
and R.sup.2 are both butyl or a pharmaceutically acceptable salt or
in vivo hydrolysable ester or amide formed on an available carboxy
or hydroxy group thereof.
4. A compound of formula (I) as claimed in claim 1 wherein R.sup.x
and R.sup.y are both hydrogen or a pharmaceutically acceptable salt
or in vivo hydrolysable ester or amide formed on an available
carboxy or hydroxy group thereof.
5. A compound of formula (I) as claimed in claim 1 wherein v is 0
or a pharmaceutically acceptable salt or in vivo hydrolysable ester
or amide formed on an available carboxy or hydroxy group
thereof.
6. A compound of formula (I) as claimed in claim 1 wherein R.sup.3
and R.sup.6 are both hydrogen or a pharmaceutically acceptable salt
or in vivo hydrolysable ester or amide formed on an available
carboxy or hydroxy group thereof.
7. A compound of formula (I) as claimed in claim 1 wherein R.sup.4
is methylthio or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide formed on an available carboxy or
hydroxy group thereof.
8. A compound of formula (I) as claimed in claim 1 wherein R.sup.5
is a group of formula (IA) (as depicted in claim 1) wherein: X is
--O--; Ring A is aryl; wherein Ring A is optionally substituted on
carbon by one or more substituents selected from R.sup.18; R.sup.7
is hydrogen; R.sup.8 is hydrogen; R.sup.9 is hydrogen; R.sup.10 is
a group of formula (IB) (as depicted in claim 1): R.sup.11 is
hydrogen; R.sup.12 and R.sup.13 are independently selected from
hydrogen or C.sub.1-10alkyl; R.sup.14 is selected from
C.sub.1-10alkyl carbocyclylC.sub.1-10alkyl and heterocyclyl;
wherein R.sup.14 may be optionally substituted on carbon by one or
more substituents selected from R.sup.29; or R.sup.14 is a group of
formula (IC) (as depicted in claim 1); R.sup.15 and R.sup.16
together with the nitrogen to which they are attached form a
heterocyclyl; wherein said heterocyclyl may be optionally
substituted on carbon by one or more R.sup.37; n is 1; R.sup.18,
R.sup.29 and R.sup.37 are independently selected from hydroxy and
N--(C.sub.1-10alkyl)carbamoyl; wherein R.sup.18, R.sup.29 and
R.sub.37 may be independently optionally substituted on carbon by
one or more R.sup.34; and R.sup.34 is carbamoyl.
9. A compound of formula (I) as claimed in claim 1 wherein: R.sup.v
is selected from hydrogen; R.sup.1 and R.sup.2are both butyl;
R.sup.x and R.sup.y are both hydrogen; v is 0; R.sup.3 and R.sup.6
are both hydrogen; R.sup.4 is methylthio; and R.sup.5 is selected
from:
N-{(R)-.alpha.-[N-2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)car-
bamoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)ca-
rbamoyl]-4-hydroxybenzyl}carbamoylmethoxy;
N-((R/S)-.alpha.-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2--
yl]carbamoyl}4-hydroxybenzyl)carbamoylmethoxy;
N---[(R)-.alpha.-(N-{2-(S)-[N-(carbamoylmethyl)carbamoyl]pyrrolidin-1-ylc-
arbonylmethyl}carbamoyl)benzyl]carbamoylmethoxy;
N-((R)-.alpha.-{N-[2-(3,4,5-trihydroxyphenyl)ethyl]carbamoyl}benzyl)carba-
moylmethoxy; and
N-{(R)-.alpha.-[N-(2-(R)-3-(S)-4-(S)-5-(R)-3,4,5,6-tetrahydroxytetrahydro-
pyran-2-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy; or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide formed on an available carboxy or hydroxy group thereof.
10. A compound of formula (I) selected from:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(S)-3-
-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmet-
hoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(S)-3-
-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}ca-
rbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-.alpha.-{N-[1-(R)-
-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenz-
yl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-.alpha.-(N-{2-(S)-[-
N-(carbamoylmethyl)
carbamoyl]pyrrolidin-1-ylcarbonylmethyl}carbamoyl)benzyl]carbamoylmethoxy-
}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-{N-[2-(3,4,-
5-trihydroxyphenyl)ethyl]carbamoyl}benzyl)carbamoylmethoxyl]-2,3,4,5-tetra-
hydro-1,2,5-benzothiadiazepine; and
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(R)-3-
-(S)-4(S)-5-(R)-3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethyl)carbamoyl]b-
enzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester
or amide formed on an available carboxy or hydroxy group
thereof.
11. A process for preparing a compound of formula (I) as claimed in
claim 1 or a pharmaceutically acceptable salt thereof which process
comprises of: Process 1): for compounds of formula (I) wherein X is
--O--, --NR.sup.a or --S--; reacting a compound of formula (IIa) or
(IIb): ##STR00028## with a compound of formula (III): ##STR00029##
wherein L is a displaceable group; Process 2): reacting an acid of
formula (IVa) or (IVb): ##STR00030## or an activated derivative
thereof; with an amine of formula (V): ##STR00031## Process 3): for
compounds of formula (I) wherein R.sup.10 is a group of formula
(IB); reacting a compound of formula (VIa): ##STR00032## or (VIb):
##STR00033## with an amine of formula (VII): ##STR00034## Process
4) for compounds of formula (I) wherein one of R.sup.4 and R.sup.5
are independently selected from C.sub.1-6alkylthio optionally
substituted on carbon by one or more R.sup.17; reacting a compound
of formula (VIIIa) or (VIIIb): ##STR00035## wherein L is a
displaceable group; with a thiol of formula (IX): R.sup.m--H (IX)
wherein R.sup.m is C.sub.1-6alkylthio optionally substituted on
carbon by one or more R.sup.17; or Process 5): for compounds of
formula (I) wherein R.sup.14 is a group of formula (IC); reacting a
compound of formula (Xa): ##STR00036## or (Xb): ##STR00037## with
an amine of formula (XI): ##STR00038## and thereafter option: i)
converting a compound of the formula (I) into another compound of
the formula (I); and/or ii) removing any protecting groups; and/or
iii) forming a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide formed on an available carboxy or
hydroxy group of said compound.
12. A pharmaceutical composition which comprises a compound of
formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide formed on an available carboxy or
hydroxy group thereof, as claimed in any one of claims 1 to 10, in
association with a pharmaceutically-acceptable diluent or carrier.
Description
This application is a Section 371 US National Stage application of
PCT/GB03/01742, filed Apr. 23, 2003.
This invention relates to benzothiadiazepine derivatives, or
pharmaceutically acceptable salts, solvates, solvates of such salts
and prodrugs thereof. These benzothiadiazepines possess ileal bile
acid transport (IBAT) inhibitory activity and accordingly have
value in the treatment of disease states associated with
hyperlipidaemic conditions and they are useful in methods of
treatment of a warm-blooded animal, such as man. The invention also
relates to processes for the manufacture of said benzothiadiazepine
derivatives, to pharmaceutical compositions containing them and to
their use in the manufacture of medicaments to inhibit IBAT in a
warm-blooded animal, such as man.
It is well-known that hyperlipidaemic conditions associated with
elevated concentrations of total cholesterol and low-density
lipoprotein cholesterol are major risk factors for cardiovascular
atherosclerotic disease (for instance "Coronary Heart Disease:
Reducing the Risk; a Worldwide View" Assman G., Carmena R. Cullen
P. et al; Circulation 1999, 100, 1930 1938 and "Diabetes and
Cardiovascular Disease: A Statement for Healthcare Professionals
from the American Heart Association" Grundy S, Benjamin L., Burke
G., et al; Circulation, 1999, 100, 1134 46). Interfering with the
circulation of bile acids within the lumen of the intestinal tracts
is found to reduce the level of cholesterol. Previous established
therapies to reduce the concentration of cholesterol involve, for
instance, treatment with HMG-CoA reductase inhibitors, preferably
statins such as simvastatin and fluvastatin, or treatment with bile
acid binders, such as resins. Frequently used bile acid binders are
for instance cholestyramine and cholestipol. One recently proposed
therapy ("Bile Acids and Lipoprotein Metabolism: a Renaissance for
Bile Acids in the Post Statin Era" Angelin B, Eriksson M, Rudling
M; Current Opinion on Lipidology, 1999, 10, 269 74) involved the
treatment with substances with an IBAT inhibitory effect.
Re-absorption of bile acid from the gastro-intestinal tract is a
normal physiological process which mainly takes place in the ileum
by the IBAT mechanism. Inhibitors of IBAT can be used in the
treatment of hypercholesterolaemia (see for instance "Interaction
of bile acids and cholesterol with nonsystemic agents having
hypocholesterolaemic properties", Biochemica et Biophysica Acta,
1210 (1994) 255 287). Thus, suitable compounds having such
inhibitory IBAT activity are also useful in the treatment of
hyperlipidaemic conditions. Compounds possessing such IBAT
inhibitory activity have been described, see for instance the
compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO
96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO
99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO
00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO
00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO
01/68906 and EP 0 864 582.
A further aspect of this invention relates to the use of the
compounds of the invention in the treatment of dyslipidemic
conditions and disorders such as hyperlipidaemia,
hypertrigliceridemia, hyperbetalipoproteinemia (high LDL),
hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia,
hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and
hypoalphalipoproteinemia (low HDL). In addition, these compounds
are expected to be useful for the prevention and treatment of
different clinical conditions such as atherosclerosis,
arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular
dysfunction, endothelial dysfunction, heart failure, coronary heart
diseases, cardiovascular diseases, myocardial infarction, angina
pectoris, peripheral vascular diseases, inflammation of
cardiovascular tissues such as heart, valves, vasculature, arteries
and veins, aneurisms, stenosis, restenosis, vascular plaques,
vascular fatty streaks, leukocytes, monocytes and/or macrophage
infiltration, intimal thickening, medial thinning, infectious and
surgical trauma and vascular thrombosis, stroke and transient
ischaemic attacks.
The present invention is based on the discovery that certain
benzothiadiazepine compounds surprisingly inhibit IBAT. Such
properties are expected to be of value in the treatment of disease
states associated with hyperlipidaemic conditions.
Accordingly, the present invention provides a compound of formula
(I):
##STR00001## wherein:
R.sup.v is selected from hydrogen or C.sub.1-6alkyl;
One of R.sup.1 and R.sup.2 are selected from hydrogen or
C.sub.1-6alkyl and the other is selected from C.sub.1-6alkyl;
R.sup.x and R.sup.y are independently selected from hydrogen,
hydroxy, amino, mercapto, C.sub.1-6alkyl, C.sub.1-6-alkoxy,
N--(C.sub.1-6-alkyl)amino, N,N--(C.sub.1-6alkly).sub.2amino,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2;
R.sup.2 is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6-alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl and N,N--(C.sub.1-6alkyl.sub.2
sulphamoyl;
v is 0 5;
one of R.sup.4 and R.sup.5 is a group of formula (IA):
##STR00002##
R.sup.3 and R.sup.6 and the other of R.sup.4 and R.sup.5 are
independently selected from hydrogen, halo, nitro, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkly).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-4alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl)sulphamoyl; wherein R.sup.3 and R.sup.6 and
the other of R.sup.4 and R.sup.5 may be optionally substituted on
carbon by one or more R.sup.17;
X is --O--, --N(R.sup.a)--, --S(O).sub.b-- or --CH(R.sup.a)--;
wherein R.sup.1 is hydrogen or C.sub.1-6alkyl and b is 0 2;
Ring A is aryl or heteroaryl; wherein Ring A is optionally
substituted on carbon by one or more substituents selected from
R.sup.18; R.sup.7 is hydrogen, C.sub.1-6alkyl, carbocyclyl or
heterocyclyl; wherein R.sup.7 is optionally substituted on carbon
by one or more substituents selected from R.sup.19; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.20;
R.sup.8 is hydrogen or C.sub.1-6alkyl;
R.sup.9 is hydrogen or C.sub.1-6-alkyl;
R.sup.10 is hydrogen, halo, nitro, cyano, hydroxy, amino,
carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.1-10alkoxy, C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heteroyclylC.sub.1-10alkyl,
carbocyclyl-C.sub.1-10alkylene).sub.p-R.sup.21-(C.sub.1-10alkylene).sub.q-
- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.22--(C.sub.1-10alkylene-
).sub.s-; wherein R.sup.10 is optionally substituted on carbon by
one or more substituents selected from R.sup.23; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen maybe
optionally substituted by a group selected from R.sup.24; or
R.sup.10 is a group of formula IB):
##STR00003## wherein:
R.sup.11 is hydrogen or C.sub.1-6alkyl;
R.sup.12 and R.sup.13 are independently selected from hydrogen,
halo, carbamoyl sulphamoyl C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl or
heterocyclyl; wherein R.sup.12 and R.sup.13 may be independently
optionally substituted on carbon by one or more substituents
selected from R.sup.25; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen maybe optionally substituted by a
group selected from R.sup.26; R.sup.14 is selected from hydrogen,
halo, carbamoyl, sulphamoyl, hydroxyaminocarbonyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkanoyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.27--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.28--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.14 may be optionally substituted on
carbon by one or more substituents selected from R.sup.29; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.30; or R.sup.14 is a group of formula (IC):
##STR00004##
R.sup.15 is hydrogen or C.sub.1-6alkyl; and R.sup.16 is hydrogen or
C.sub.1-6alkyl; wherein R.sup.16 may be optionally substituted on
carbon by one or more groups selected from R.sup.31; or R.sup.15
and R.sup.16 together with the nitrogen to which they are attached
form a heterocyclyl; wherein said heterocyclyl may be optionally
substituted on carbon by one or more R.sup.37; and wherein if said
heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.38;
n is 1 3; wherein the values of R.sup.7 may be the same or
different;
R.sup.17, R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29,
R.sup.31 and R.sup.37 are independently selected from halo, nitro,
cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, N--(C.sub.1-10alkyl)amino,
N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.32--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.33--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.17, R.sup.18, R.sup.19, R.sup.23,
R.sup.25, R.sup.29, R.sup.31 and R.sup.37 may be independently
optionally substituted on carbon by one or more R.sup.34; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.35;
R.sup.21, R.sup.22, R.sup.27, R.sup.28, R.sup.32 or R.sup.33 are
independently selected from --O--, --NR.sup.36--, --S(O).sub.x--,
--NR.sup.36C(O)NR.sup.36--, --NR.sup.36C(S)NR.sup.36--,
--OC(O)N.dbd.C--, --NR.sup.36C(O)-- or --C(O)NR.sup.36--; wherein
R.sup.36 is selected from hydrogen or C.sub.1-6alkyl, and x is 0
2;
p, q, r and s are independently selected from 0 2;
R.sup.34 is selected from halo, hydroxy, cyano, carbamoyl, ureido,
amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,
trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl,
ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy,
methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino
and N,N-dimethylsulphamoylamino;
R.sup.20, R.sup.24, R.sup.26, R.sup.30, R.sup.35 and R.sup.38 are
independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6-alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkylcarbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
A further aspect of the invention provides a compound of formula
(I):
##STR00005## wherein:
R.sup.v is selected from hydrogen or C.sub.1-6alkyl;
One of R.sup.1 and R.sup.2 are selected from hydrogen or
C.sub.1-6alkyl and the other is selected from C.sub.1-6alkyl;
R.sup.x and R.sup.y are independently selected from hydrogen,
hydroxy, amino, mercapto, C.sub.1-6alkly, C.sub.1-6alkoxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2;
R.sup.z is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl;
v is 0 5;
one of R.sup.4 and R.sup.5 is a group of formula (IA):
##STR00006##
R.sup.3 and R.sup.6 and the other of R.sup.4 and R.sup.5 are
independently selected from hydrogen, halo, nitro, cyano, hydroxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; wherein R.sup.3 and R.sup.6
and the other of R.sup.4 and R.sup.5 may be optionally substituted
on carbon by one or more R.sup.17;
X is --O--, --N(R.sup.a)--, --S(O).sub.b-- or --CH(R.sup.a)--;
wherein R.sup.a is hydrogen or C.sub.1-6alkyl and b is 0 2;
Ring A is aryl or heteroaryl; wherein Ring A is optionally
substituted on carbon by one or more substituents selected from
R.sup.18;
R.sup.7 is hydrogen, C.sub.1-6alkyl, carbocyclyl or heterocyclyl;
wherein R.sup.7 is optionally substituted on carbon by one or more
substituents selected from R.sup.19; and wherein if said
heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.20;
R.sup.8 is hydrogen or C.sub.1-6alkyl;
R.sup.9 is hydrogen or C.sub.1-6alkly;
R.sup.10 is hydrogen, halo, nitro, cyano, hydroxy, amino,
carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.1-10alkoxy, C.sub.1-10alkanoyl, C.sub.1-10alkanoyloxy,
N--(C.sub.1-10alkyl)amino, N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl,
carbocyclylC.sub.1-10alkyl, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.21--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.22--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.10 is optionally substituted on carbon by
one or more substituents selected from R.sup.23; and wherein if
said heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.24; or
R.sup.10 is a group of formula (IB):
##STR00007## wherein:
R.sup.11 is hydrogen or C.sub.1-6alkyl;
R.sup.12 and R.sup.13 are independently selected from hydrogen,
halo, carbamoyl, sulphamoyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl or
heterocyclyl; wherein R.sup.12 and R.sup.13 may be independently
optionally substituted on carbon by one or more substituents
selected from R.sup.25; and wherein if said heterocyclyl contains
an --NH-- group, that nitrogen may be optionally substituted by a
group selected from R.sup.26;
R.sup.14 is selected from hydrogen, halo, carbamoyl, sulphamoyl,
hydroxyaminocarbonyl, C.sub.1-10alkyl, C.sub.1-10alkenyl,
C.sub.1-10alkynyl, C.sub.1-10alkanoyl,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl).sub.2sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino, carbocyclyl,
carbocyclylC.sub.1-10, heterocyclyl, heterocyclylC.sub.1-10alkyl,
carbocyclyl-(C.sub.1-10alkylene).sub.p-R.sup.27--(C.sub.1-10alkylene).sub-
.q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.28--(C.sub.1-10alkyle-
ne).sub.s-; wherein R.sup.14 may be optionally substituted on
carbon by one or more substituents selected from R.sup.29; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.30; or R.sup.14 is a group of formula (IC):
##STR00008##
R.sup.15 is hydrogen or C.sub.1-6alkyl;
R.sup.16 is hydrogen or C.sub.1-6alkyl; wherein R.sup.16 may be
optionally substituted on carbon by one or more groups selected
from R.sup.31;
n is 1 3; wherein the values of R.sup.7 may be the same or
different;
R.sup.17, R.sup.18, R.sup.19, R.sup.23, R.sup.25, R.sup.29 or
R.sup.31 are independently selected from halo, nitro, cyano,
hydroxy, amino, carbamoyl, mercapto, sulphamoyl,
hydroxyaminocarbonyl C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, C.sub.1-10alkoxy, C.sub.1-10alkanoyl,
C.sub.1-10alkanoyloxy, N--(C.sub.1-10alkyl)amino,
N,N--(C.sub.1-10alkyl).sub.2amino,
N,N,N--(C.sub.1-10alkyl).sub.3ammonio, C.sub.1-10alkanoylamino,
N--(C.sub.1-10alkyl)carbamoyl,
N,N--(C.sub.1-10alkyl).sub.2carbamoyl, C.sub.1-10alkylS(O).sub.a
wherein a is 0 to 2, N--(C.sub.1-10alkyl)sulphamoyl,
N,N--(C.sub.1-10alkyl)sulphamoyl,
N--(C.sub.1-10alkyl)sulphamoylamino,
N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino,
C.sub.1-10alkoxycarbonylamino, carbocyclyl
carbocyclylC.sub.1-10alkly, heterocyclyl,
heterocyclylC.sub.1-10alkyl,
carbocyclyl(C.sub.1-10alkylene).sub.p-R.sup.32--(C.sub.1-10alkylene).sub.-
q- or
heterocyclyl-(C.sub.1-10alkylene).sub.r-R.sup.33--(C.sub.1-10alkylen-
e).sub.s-; wherein R.sup.17, R.sup.18, R.sup.19, R.sup.23,
R.sup.25, R.sup.29 or R.sup.31 may be independently optionally
substituted on carbon by one or more R.sup.34; and wherein if said
heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.35;
R.sup.21, R.sup.22, R.sup.27, R.sup.28, R.sup.32 or R.sup.33 are
independently selected from --O--, --NR.sup.36--, --S(O).sub.x--,
--NR.sup.36C(O)NR.sup.36--, --NR.sup.36C(S)NR.sup.36--,
--OC(O)N.dbd.C--, --NR.sup.36C(O)-- or --C(O)NR.sup.36--; wherein
R.sup.36 is selected from hydrogen or C.sub.1-6alkyl, and x is 0
2;
p, q, r and s are independently selected from 0 2;
R.sup.34 is selected from halo, hydroxy, cyano, carbamoyl, ureido,
amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,
trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl,
ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy,
methylamino, dimethylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,
N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino
and N,N-dimethylsulphamoylamino;
R.sup.20, R.sup.24, R.sup.26, R.sup.30 or R.sup.35 are
independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
In this specification the term "alkyl" includes both straight and
branched chain alkyl groups but references to individual alkyl
groups such as "propyl" are specific for the straight chain version
only. For example, "C.sub.1-6alkyl" includes C.sub.1-4alkyl,
C.sub.1-3alkyl, propyl, isopropyl and t-butyl. However, references
to individual alkyl groups such as `propyl` are specific for the
straight chained version only and references to individual branched
chain alkyl groups such as `isopropyl` are specific for the
branched chain version only. A similar convention applies to other
radicals, for example "phenylC.sub.1-6alkyl" would include
phenylC.sub.1-6alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The
term "halo" refers to fluoro, chloro, bromo and iodo.
Where optional substituents are chosen from "one or more" groups it
is to be understood that this definition includes all substituents
being chosen from one of the specified groups or the substituents
being chosen from two or more of the specified groups.
"Heteroaryl" is a totally unsaturated, mono or bicyclic ring
containing 3 12 atoms of which at least one atom, particularly 1 3
atoms, are chosen from nitrogen, sulphur or oxygen, which may,
unless otherwise specified, be carbon or nitrogen linked.
Preferably "heteroaryl" refers to a totally unsaturated, monocyclic
ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10
atoms of which at least one atom is chosen from nitrogen, sulphur
or oxygen, which may, unless otherwise specified, be carbon or
nitrogen linked. Examples and suitable values of the term
n"heteroaryl" are thienyl, isoxazolyl, imidazolyl, pyrrolyl,
thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyridyl and quinolyl. Preferably the term
"heteroaryl" refers to thienyl or indolyl. "Heteroaryl" is not
tetrazolyl.
"Aryl" is a totally unsaturated, mono or bicyclic carbon ring that
contains 3 12 atoms. Preferably "aryl" is a monocyclic ring
containing 5 or 6 atoms or a bicyclic ring containing 9 or 10
atoms. Suitable values for "aryl" include phenyl or naphthyl.
Particularly "aryl" is phenyl.
A "heterocyclyl" is a saturated, partially saturated or
unsaturated, mono or bicyclic ring containing 3 12 atoms of which
at least one atom, particularly 1 3 atoms, are chosen from
nitrogen, sulphur or oxygen, which may, unless otherwise specified,
be carbon or nitrogen linked, wherein a --CH.sub.2-- group can
optionally be replaced by a --C(O)-- or a ring sulphur atom may be
optionally oxidised to form the S-oxides. Preferably a
"heterocyclyl" is a saturated, partially saturated or unsaturated,
mono or bicyclic ring containing 5 or 6 atoms of which at least one
atom is chosen from nitrogen, sulphur or oxygen, which may, unless
otherwise specified, be carbon or nitrogen linked, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- or a
ring sulphur atom may be optionally oxidised to form S-oxide(s).
Examples and suitable values of the term "heterocyclyl" are
thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl,
2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl,
1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,
2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6 dihydrouracilyl,
1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl,
4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl,
tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl,
tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl,
piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino,
tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl,
isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl,
1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl,
thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl
and 1-isoquinolonyl. "Heterocyclyl" is not tetrazolyl.
A "carbocyclyl" is a saturated, partially saturated or unsaturated,
mono or bicyclic carbon ring that contains 3 12 atoms; wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)--.
Preferably "carbocyclyl" is a monocyclic ring containing 5 or 6
atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values
for "carbocyclyl" include cyclopropyl, cyclobutyl,
1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or
1-oxoindanyl. Particularly "carbocyclyl" is cyclopropyl,
cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, phenyl or 1-oxoindanyl.
An example of "C.sub.1-10alkanoyloxy" and "C.sub.1-6alkanoyloxy" is
acetoxy. Examples of "C.sub.1-10alkoxycarbonyl" and
"C.sub.1-6alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl,
n- and t-butoxycarbonyl. Examples of "C.sub.1-10alkoxy" and
"C.sub.1-6alkoxy" include methoxy, ethoxy and propoxy. Examples of
"C.sub.1-10alkanoylamino" and "C.sub.1-6alkanoylamino" include
formamido, acetamido and propionylamino. Examples of
"C.sub.1-10alkylS(O).sub.a wherein a is 0 to 2" and
"C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2" include methylthio,
ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and
ethylsulphonyl. Examples of "C.sub.1-10alkanoyl" and
"C.sub.1-6alkanoyl" include C.sub.1-3alkanoyl, propionyl and
acetyl. Examples of "N--C.sub.1-10alkylamino" and
"N--C.sub.1-6alkylamino" include methylamino and ethylamino.
Examples of "N,N--(C.sub.1-10alkyl).sub.2amino" and
"N,N--(C.sub.1-6alkyl).sub.2amino" include di-N-methylamino,
di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of
"C.sub.2-10alkenyl" and "C.sub.2-6alkenyl" are vinyl, allyl and
1-propenyl. Examples of "C.sub.2-10alkyl" and "C.sub.2-6alkynyl"
are ethynyl, 1-propynyl and 2-propynyl. Examples of
"N--(C.sub.1-10alkyl)sulphamoyl" and
"N--(C.sub.1-6alkyl)sulphamoyl" are N--(C.sub.1-3alkyl)sulphamoyl,
N(methyl)sulphamoyl and N-ethyl)sulphamoyl. Examples of
"N--(C.sub.1-10alkyl).sub.2sulphamoyl" and
"N--(C.sub.1-6alkyl).sub.2sulphamoyl" are N,N-(dimethyl)sulphamoyl
and N-(methyl)-N-(ethyl)sulphamoyl. Examples of
"N--(C.sub.1-10alkyl)carbamoyl" and "N--(C.sub.1-6alkyl)carbamoyl"
are methylaminocarbonyl and ethylaminocarbonyl. Examples of
"N,N--(C.sub.1-10alkyl)carbamoyl" and
"N,N--(C.sub.1-6alkylcarbamoyl" are dimethylaminocarbonyl and
methylethylaminocarbonyl. Example of "C.sub.1-10alkylsulphonyl" and
"C.sub.1-6-alkylsulphonyl" are mesyl and ethylsulphonyl. Examples
of "N,N,N--(C.sub.1-10alkyl).sub.3ammonio" and
"N,N,N--(C.sub.1-6alkyl).sub.3ammonio" are trimethylamino and
methyldiethylamino. Examples of "C.sub.1-10alkoxycarbonylamino" and
"C.sub.1-6alkoxycarbonylamino" are methoxycarbonylamino and
t-butoxycarbonylamino. Examples of
"N--(C.sub.1-10alkyl)sulphamoylamino" and
"N--(C.sub.1-6alkyl)sulphamoylamino" are N-methylsulphamoylamino
and N-ethylsulphamoylamino. Examples of
"N,N--(C.sub.1-10alkyl).sub.2sulphamoylamino" and
"N,N--(C.sub.1-6alkyl).sub.2sulphamoylamino" are
N,N-dimethylsulphamoylamino and N-methyl-N-ethylsulphamoylamino.
Examples of "C.sub.1-10alkylthio" and "C.sub.1-6alkylthio" are
methylthio and ethylthio. Examples of "carbocyclylC.sub.1-10alkyl"
include benzyl and phenethyl. Examples of
"heterocyclylC.sub.1-10alkyl" include morphoinopropyl and
pyridylmethyl.
A suitable pharmaceutically acceptable salt of a compound of the
invention is, for example, an acid-addition salt of a compound of
the invention which is sufficiently basic, for example, an
acid-addition salt with, for example, an inorganic or organic acid,
for example hydrochloric, hydrobromic, sulphuric, phosphoric,
trifluoroacetic, citric, acetate or maleic acid. In addition a
suitable pharmaceutically acceptable salt of a compound of the
invention which is sufficiently acidic is an alkali metal salt, for
example a sodium or potassium salt, an alkaline earth metal salt,
for example a calcium or magnesium salt, an ammonium salt or a salt
with an organic base which affords a physiologically-acceptable
cation, for example a salt with methylamine, dimethylamine,
trimethylamine, piperidine, morpholine or
tris-(2-hydroxyethyl)amine.
The compounds of the formula (I) may be administered in the form of
a pro-drug which is broken down in the human or animal body to give
a compound of the formula (I). examples of pro-rugs include in vivo
hydrolysable esters and in vivo hydrolysable amides of a compound
of the formula (I).
An in vivo hydrolysable ester of a compound of the formula (I)
containing carboxy or hydroxy group is, for example, a
pharmaceutically acceptable ester which is hydrolysed in the human
or animal body to produce the parent acid or alcohol. Suitable
pharmaceutically acceptable esters for carboxy include
C.sub.1-6alkoxymethyl esters for example methoxymethyl,
C.sub.1-6alkanoyloxymethyl esters for example pivaloyloxymethyl,
phthalidyl esters, C.sub.3-8cycloalkoxycarbonyloxyC.sub.1-6alkyl
esters for example 1-cyclohexylcarbonyloxyethyl;
1,3-dioxolen-2-onylmethyl esters for example
5-methyl-1,3-dioxolen-2onylmethyl; and
C.sub.1-6alkoxycarbonyloxyethyl esters for example
1-methoxycarbonyloxyethyl and may be formed at any carboxy group in
the compounds of this invention.
An in viva hydrolysable ester of a compound of the formula (I)
containing a hydroxy group includes inorganic esters such as
phosphate esters and .alpha.-acyloxyalkyl ethers and related
compounds which as a result of the in vivo hydrolysis of the ester
breakdown to give the parent hydroxy group. Examples of
.alpha.-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxy-methoxy. A selection of in vivo
hydrolysable ester forming groups for hydroxy include alkanoyl,
benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,
alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl
and N-(dialkylaminoethyl)N-alkylcarbamoyl (to give carbamates),
dialkylaminoacetyl and carboxyacetyl. Examples of substituents on
benzoyl include morpholino and piperazino linked from a ring
nitrogen atom via a methylene group to the 3- or 4-position of the
benzoyl ring.
A suitable value for an in vivo hydrolysable amide of a compound of
the formula (I) containing a carboxy group is, for example, a
N--C.sub.1-6alkyl or N,N-di-C.sub.1-6alkyl amide such as NV-methyl,
N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-ethyl
amide.
Some compounds of the formula (I) may have chiral centres and/or
geometric isomeric centres (E- and Z-isomers), and it is to be
understood that the invention encompasses all such optical,
diastereoisomers and geometric isomers that possess IBAT inhibitory
activity.
The invention relates to any and all tautomeric forms of the
compounds of the formula (I) that possess IBAT inhibitory
activity.
It is also to be understood that certain compounds of the formula
(I) can exist in solvated as well as unsolvated forms such as, for
example, hydrated forms. It is to be understood that the invention
encompasses all such solvated forms which possess IBAT inhibitory
activity.
Particular values are as follows. Such values may be used where
appropriate with any of the definitions, claims or embodiments
defined hereinbefore or hereinafter.
R.sup.v is selected from hydrogen.
R.sup.1 and R.sup.2 are both C.sub.1-6alkyl.
R.sup.1 and R.sup.2 are both C.sub.1-4alkyl.
One of R.sup.1 and R.sup.2 is ethyl and the other is butyl.
R.sup.1 and R.sup.2 are both butyl.
R.sup.x and R.sup.y are both hydrogen.
R.sup.z is C.sub.1-4alkyl.
v is 0 2.
v is 0.
R.sup.4 is a group of formula (IA).
R.sup.5 is a group of formula (IA).
R.sup.3 and R.sup.6 are hydrogen.
R.sup.4 is halo.
R.sup.4 is bromo or chloro.
R.sup.4 is C.sub.1-6alkoxy.
R.sup.4 is ethoxy or methoxy.
R.sup.4 is methoxy.
R.sup.4 is ethylthio or methylthio.
R.sup.4 is methylthio.
R.sup.5 is methylthio.
R.sup.5 is a group of formula (IA) and R.sup.4 is
C.sub.1-6alkylS(O).sub.a wherein a is 0.
R.sup.5 is a group of formula (IA) and R.sup.4 is
C.sub.1-4alkylS(O).sub.a wherein a is 0.
R.sup.5 is a group of formula (IA) and R.sup.4 is methylthio.
X is 13 O--.
Ring A is aryl; wherein Ring A is optionally substituted on carbon
by one or more substituents selected from R.sup.18; wherein
R.sup.18 is hydroxy.
Ring A is phenyl; wherein Ring A is optionally substituted on
carbon by one or more substituents selected from R.sup.18; wherein
R.sup.18 is hydroxy.
Ring A is phenyl or 4hydroxyphenyl.
R.sup.7 is hydrogen.
R.sup.8 is hydrogen.
R.sup.9 is hydrogen.
R.sup.10 is a group of formula (IB).
R.sup.11 is hydrogen.
R.sup.12 and R.sup.13 are independently selected from hydrogen or
C.sub.1-10alkyl.
R.sup.12 and R.sup.13 are independently selected from hydrogen or
C.sub.1-4alkyl.
R.sup.12 and R.sup.13 as independently selected from hydrogen or
methyl.
R.sup.12 and R.sup.13 are both hydrogen or one of R.sup.12 and
R.sup.13 is hydrogen and the other is methyl.
R.sup.14 is selected from C.sub.1-10alkyl or
carbocyclylC.sub.1-10alkyl; wherein R.sup.14 may be optionally
substituted on carbon by one or more substituents selected from
R.sup.29; wherein R.sup.29 is hydroxy.
R.sup.14 is selected from C.sub.1-10alkyl,
carbocyclylC.sub.1-10alkyl and heterocyclylC.sub.1-10alkyl; wherein
R.sup.14 may be optionally substituted on carbon by one or more
substituents selected from R.sup.29; wherein R.sup.29 is hydroxy;
or R.sup.14 is a group of formula (IC) (as depicted above).
R.sup.14 is selected from C.sub.1-6alkyl or phenylC.sub.1-4alkyl;
wherein R.sup.14 may be optionally substituted on carbon by one or
more substituents selected from R.sup.29; wherein R.sup.29 is
hydroxy.
R.sup.14 is selected from pentyl, benzyl and tetrahydropyran;
wherein R.sup.14 may be optionally substituted on carbon by one or
more substituents selected from R.sup.29; wherein R.sup.29 is
hydroxy; or R.sup.14 is a group of formula (IC) (as depicted
above).
R.sup.14 is selected from pentyl or benzyl; wherein R.sup.14 may be
optionally substituted on carbon by one or more substituents
selected from R.sup.29; wherein R.sup.29 is hydroxy.
R.sup.14 is selected from 1,2,3,4,5-pentahydroxypentyl or
3,4-dihydroxybenzyl.
R.sup.15 and R.sup.16 together with the nitrogen to which they are
attached form a heterocyclyl; wherein said heterocyclyl may be
optionally substituted on carbon by one or more R.sup.37; wherein
R.sup.37 is N--(C.sub.1-10alkyl)carbamoyl; optionally substituted
on carbon by one or more R.sup.34; wherein R.sup.34 is
carbamoyl.
R.sup.15 and R.sup.16 together with the nitrogen to which they are
attached form pyrrolidinyl; wherein said pyrrolidinyl may be
optionally substituted on carbon by one or more R.sup.37; R.sup.37
is N-methylcarbamoyl; optionally substituted on carbon by one or
more R.sup.34; wherein R.sup.34 is carbamoyl.
R.sup.15 and R.sup.16 together with the nitrogen to which they are
attached form 2(N-(carbamoylmethyl)carbamoylpyrrolidin-1-yl.
n is 1.
R.sup.5 is a group of formula (IA) as depicted above wherein:
X is --O--;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
Ring A is aryl;
R.sup.10 is carbamoyl or N--(C.sub.1-10alkyl)carbamoyl or a group
of formula (IB) (as depicted above) wherein R.sup.10 is optionally
substituted on carbon by one or more substituents selected from
R.sup.23 and wherein:
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen,
carbamoyl or C.sub.1-6alkyl; wherein R.sup.12 and R.sup.13 may be
independently optionally substituted on carbon by one or more
substituents selected from R.sup.25;
R.sup.14 is selected from carbamoyl, hydroxyaminocarbonyl,
C.sub.1-6alkyl, carbocyclyl, carbocyclylC.sub.1-10alkyl,
heterocyclyl, heterocyclylC.sub.1-10alkyl or
carbocyclyl-C.sub.1-6alkylene).sub.p-R.sup.27--(C.sub.1-6alkylene).sub.q--
; wherein R.sup.14 may be optionally substituted on carbon by one
or more substituents selected from R.sup.29; and wherein if said
heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.30; or
R.sup.14 is a group of formula (IC) (as depicted above)
wherein:
R.sup.15 is hydrogen or C.sub.1-6alkyl;
R.sup.16 is C.sub.1-6alkyl; wherein R.sup.16 may be optionally
substituted on carbon by one or more groups selected from
R.sup.31;
n is 1;
R.sup.23 is hydroxy;
R.sup.25, R.sup.29 or R.sup.31 are independently selected from
halo, hydroxy, amino, sulphamoyl, C.sub.1-6alkoxy,
N,N,N--(C.sub.1-6alkyl).sub.3ammonio,
N,N--(C.sub.1-6alkyl).sub.2sulphamoylamino,
C.sub.1-6alkoxycarbonylamino, carbocyclyl, heterocyclyl,
carbocyclyl-(C.sub.1-6alkylene).sub.p-R.sup.32--(C.sub.1-6alkylene).sub.q-
- or
heterocyclyl-C.sub.1-6alkylene).sub.r-R.sup.33--(C.sub.1-6alkylene).s-
ub.s-; wherein R.sup.25, R.sup.29 or R.sup.31 may be independently
optionally substituted on carbon by one or more R.sup.34; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.35;
R.sup.27, R.sup.32 or R.sup.33 are independently selected from
--O--, --NR.sup.36C(O)NR.sup.36--, --OC(O)N.dbd.C--or
--NR.sup.36C(O)--; wherein R.sup.23 is hydrogen;
p, q, r and s are independently selected from 0 or 1;
R.sup.34 is selected from hydroxy, amino, carbamoyl, sulphamoyl or
methoxy;
R.sup.30 or R.sup.35 are independently selected from C.sub.1-6alkyl
or C.sub.1-6alkoxycarbonyl.
R.sup.5 is a group of formula (IA) as depicted above wherein:
X is --O--;
Ring A is aryl; wherein Ring A is optionally substituted on carbon
by one or more substituents selected from R.sup.18;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
R.sup.10 is a group of formula (IB) (as depicted above):
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen or
C.sub.1-10alkyl;
R.sup.14 is selected from C.sub.1-10alkyl,
carbocyclylC.sub.1-10alkyl and heterocyclyl; wherein R.sup.14 may
be optionally substituted on carbon by one or more substituents
selected from R.sup.29; or R.sup.14 is a group of formula (IC) (as
depicted above);
R.sup.15 and R.sup.16 together with the nitrogen to which they are
attached form a heterocyclyl; wherein said heterocyclyl may be
optionally substituted on carbon by one or more R.sup.37;
n is 1;
R.sup.18, R.sup.29 and R.sup.37 are independently selected from
hydroxy and N--(C.sub.1-10-alkyl)carbamoyl; wherein R.sup.18,
R.sup.29 and R.sup.37 may be independently optionally substituted
on carbon by one or more R.sup.34; and
R.sup.34 is carbamoyl.
R.sup.5 is a group of formula (IA) as depicted above wherein:
X is --O--;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
Ring A is phenyl;
R.sup.10 is carbamoyl or a group of formula (IB) (as depicted
above) wherein:
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen,
carbamoyl or C.sub.1-6alkyl; wherein R.sup.12 and R.sup.13 may be
independently optionally substituted on carbon by one or more
substituents selected from R.sup.25;
R.sup.14 is selected from carbamoyl, hydroxyaminocarbonyl,
C.sub.1-6alkyl, carbocyclyl, heterocyclyl or
carbocyclyl-(C.sub.1-6alkylene).sub.p-R.sup.27--(C.sub.1-6alkylene).sub.q-
-; wherein R.sup.14 may be optionally substituted on carbon by one
or more substituents selected from R.sup.29; and wherein if said
heterocyclyl contains an --NH-- group, that nitrogen may be
optionally substituted by a group selected from R.sup.30; or
R.sup.14 is a group of formula (IC) (as depicted above)
wherein:
R.sup.15 is hydrogen;
R.sup.16 is C.sub.1-6alkyl; wherein R.sup.16 may be optionally
substituted on carbon by one or more groups selected from
R.sup.31;
n is 1;
R.sup.25, R.sup.29 or R.sup.31 are independently selected from
halo, hydroxy, amino, sulphamoyl, C.sub.1-6alkoxy,
N,N,N--(C.sub.1-6alkyl).sub.3ammonio,
N,N--(C.sub.1-6alkyl).sub.2sulphamoylamino,
C.sub.1-6alkoxycarbonylamino, carbocyclyl, heterocyclyl,
carbocyclyl-(C.sub.1-6alkylene).sub.p-R.sup.32--C.sub.1-6alkylene).sub.q-
or
heterocyclyl-(C.sub.1-6alkylene).sub.r-R.sup.33--(C.sub.1-6alkylene).s-
ub.s-; wherein R.sup.25, R.sup.29 or R.sup.31 may be independently
optionally substituted on carbon by one or more R.sup.34; and
wherein if said heterocyclyl contains an --NH-- group, that
nitrogen may be optionally substituted by a group selected from
R.sup.35;
R.sup.27, R.sup.32 or R.sup.33 are independently selected from
--O--, --NR.sup.36C(O)NR.sup.36--, --OC(O)N.dbd.C--or
--NR.sup.36C(O)--; wherein R.sup.23 is hydrogen;
p, q, r and s are independently selected from 0 or 1;
R.sup.34 is selected from hydroxy, amino, carbamoyl, sulphamoyl or
methoxy;
R.sup.30 or R.sup.35 are independently selected from C.sub.1-6alkyl
or C.sub.1-6alkoxycarbonyl.
R.sup.5is a group of formula (IA) as depicted above wherein:
X is --O--;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
R.sup.10 is carbamoyl or a group of formula (IB) (as depicted
above) wherein:
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen,
carbamoyl or methyl; wherein R.sup.12 and R.sup.13 may be
independently optionally substituted on carbon by one or more
substituents selected from R.sup.25;
R.sup.14 is selected from carbamoyl, hydroxyaminocarbonyl, methyl,
ethyl, propyl, phenyl, 1,5-benzodioxepinyl,
2,3-dihydrobenzofuranyl, piperidinyl, anilinocarbonyl or
anilinocarbonyl; wherein R.sup.14 may be optionally substituted on
carbon by one or more substituents selected from R.sup.29; and
wherein said piperidinyl may be optionally substituted on nitrogen
by a group selected from R.sup.30; or R.sup.14 is a group of
formula (IC) (as depicted above) wherein:
R.sup.15 is hydrogen;
R.sup.16 is methyl, ethyl or hexyl; wherein R.sup.16 may be
optionally substituted on carbon by one or more groups selected
from R.sup.31;
n is 1;
R.sup.25, R.sup.29 or R.sup.31 are independently selected from
fluoro, hydroxy, amino, sulphamoyl, methoxy, N,N,N-trimethylamino,
N,N-dimethylsulphamoylamino, t-butoxycarbonylamino, phenyl,
morpholino, imidazolyl, indolyl, 2,4thiazolidinedionyl,
piperazinyl, 2-imidazolidinonyl, phenoxy,
benxyloxycarbonyliminomethyl, N'-pyridinylureido or
N'-pyrimidinylureido; wherein R.sup.25, R.sup.29 or R.sup.31 may be
independently optionally substituted on carbon by one or more
R.sup.34; and wherein said imidazolyl, indolyl, piperazinyl or
2-imidazolidinonyl may be optionally substituted on nitrogen by a
group selected from R.sup.35;
R.sup.27, R.sup.32 or R.sup.33 are independently selected from
--O--, --NHC(O)NH--, --OC(O)N.dbd.C-- or --NHC(O)--;
p, q, r and s are independently selected from 0 or 1;
R.sup.34 is selected from hydroxy, amino, carbamoyl, sulphamoyl or
methoxy;
R.sup.30 or R.sup.35 are independently selected from methyl or
C.sub.1-6alkoxycarbonyl.
R.sup.5 is a group of formula (IA) as depicted above wherein:
X is --O--;
Ring A is phenyl; wherein Ring A is optionally substituted on
carbon by one or more substituents selected from R.sup.18;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
R.sup.10 is a group of formula (IB) (as depicted above):
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen or
methyl;
R.sup.14 is selected from pentyl, benzyl and tetrahydropyran;
wherein R.sup.14 may be optionally substituted on carbon by one or
more substituents selected from R.sup.29; or R.sup.14 is a group of
formula (IC) (as depicted above);
R.sup.15 and R.sup.16 together with the nitrogen to which they are
attached form pyrrolidinyl; wherein said pyrrolidinyl may be
optionally substituted on carbon by one or more R.sup.37;
n is 1;
R.sup.18, R.sup.29 and R.sup.37 are independently selected from
hydroxy and N-methylcarbamoyl; wherein R.sup.18, R.sup.29 and
R.sup.37 may be independently optionally substituted on carbon by
one or more R.sup.34; and
R.sup.34 is carbamoyl.
R.sup.5 is selected from:
N-{(R)-.alpha.-[N'-(2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(2-trimethylaminoethyl)carbamoyl]benzyl}carbamoylmetho-
xy;
N-{(R)-.alpha.-[N'-(2-aminoethyl)carbamoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(carbamoylmethyl)carbamoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N'--((S)-1-carbamoyl-2-hydroxyethyl)carbamoyl]benzyl}carb-
amoylmethoxy; N-((R)-.alpha.-carbamoylbenzyl)carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(1,1-di-hydroxymethyl-2-hydroxyethyl)carbamoyl]benzyl}-
carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(hydroxycarbamoylmethyl)carbamoyl]benzyl}carbamoylmeth-
oxy;
N-((R)-.alpha.-{N'-[N-(2,2,2-trifluoroethyl)carbamoylmethyl]carbamoyl-
}benzyl) carbamoylmethoxy;
N-((R)-.alpha.-{N'-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexy-
l)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy;
N-((R)-.alpha.-{N'-[N-(2-fluoroethyl)carbamoylmethyl]carbamoyl}benzyl)car-
bamoylmethoxy;
N-((R)-.alpha.-{N'-[N-(ethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylme-
thoxy;
N-((R)-.alpha.-{N'-[N-(4-hydroxy-3-methoxybenzyl)carbamoylmethyl]ca-
rbamoyl}benzyl) carbamoylmethoxy,
N-((R)-.alpha.-{N'-[N-(2-methoxyethyl)carbamoylmethyl]carbamoyl}benzyl)ca-
rbamoylmethoxy;
N-((R)-.alpha.-{N'-[N-(4-sulphamoylphenethyl)carbamoylmethyl]carbamoyl}be-
nzyl) carbamoylmethoxy;
N-((R)-.alpha.-{N'-[N-(2-N,N-dimethylaminosulphamoylethyl)carbamoylmethyl-
]carbamoyl}benzyl)carbamoylmethoxy;
N-[(R)-.alpha.-(N'-(N-[2-(N'-pyrimidin-2-ylreido)ethyl]carbamoylmethyl}ca-
rbamoyl)benzyl]carbamoylmethoxy;
(N-{(R)-.alpha.-[N'-(2-(S)-3-(R)-4-(R)-5-(R)-3,4,5,6-pentahydroxyhexyl)ca-
rbamoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N'-3-morpholinopropyl)carbamoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(2-imidazol-4-ylethyl)carbamoyl]benzyl}carbamoylmethox-
y;
N-{(R)-.alpha.-[N'-(2-N,N-dimethylaminosulphamoylethyl)carbamoyl]benzyl-
}carbamoylmethoxy;
N-((R)-.alpha.-{N'-[2-(2-hydroxyphenoxy)ethyl]carbamoyl}benzyl)carbamoylm-
ethoxy;
N-{(R)-.alpha.-[N'-(3-hydroxy-1,5-benzodioxepin-3-ylmethyl)carbamo-
yl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N'-3-t-butoxycarbonylaminobenzyl)carbamoyl]benzyl}carbamo-
ylmethoxy;
N-((R)-.alpha.-{N'-[3-(benxyloxycarbonylimino-1-aminomethyl)ben-
zyl]carbamoyl}benzyl) carbamoylmethoxy;
N-((R)-.alpha.-{N'-[2-(3,4-dihydroxyphenyl-2-methoxyethyl]carbamoyl}benzy-
l) carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(2,3-dihydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy-
;
N-((R)-.alpha.-{N'-[2-(5-methoxyindol-3-yl)ethyl]carbamoyl}benzyl)carbam-
oylmethoxy;
N-((R)-.alpha.-{N'-[2-(2,5-dioxothiazolidin-1-yl)ethyl]carbamoyl}benzyl)c-
arbamoylmethoxy;
N-((R)-.alpha.-{N'-[3-(-methylpiperazin-1-yl)propyl]carbamoyl}benzyl)carb-
amoylmethoxy;
N-{(R)-.alpha.-[N'-(4-sulphamoylphenethyl)carbamoyl]benzyl}carbamoylmetho-
xy;
N-{(R)-.alpha.-[N'-(5,6-dimethoxy-2,3-dihydobenzofuran-2-ylmethyl)carb-
amoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(1-t-butoxycarbonylpiperidin-4ylmethyl)carbamoyl]benzy-
l}carbamoylmethoxy;
N-{(R)-.alpha.-[N'-(4-nitroanilinocarbonylmethyl)carbamoyl]benzyl}carbamo-
ylmethoxy;
N-((R)-.alpha.-{N'-[2-(N'-pyrimidin-2-ylreido)ethyl]carbamoyl}b-
enzyl)carbamoylmethoxy;
N-((R)-.alpha.-{N'-[2-(N'-pyridin-2-ylreido)ethyl]carbamoyl}benzyl)carbam-
oylmethoxy;
N-((R)-.alpha.-{N'-[2-(4-carbamoylphenoxy)ethyl]carbamoyl}benzyl)carbamoy-
lmethoxy;
N-((R)-.alpha.-{N'-[2-(2-oxoimidazolidin-1-yl)ethyl]carbamoyl}be-
nzyl)carbamoylmethoxy; and
N-{(R)-.alpha.-[N'-(3-aminobenzyl)carbamoyl]benzyl}carbamoylmethoxy.
R.sup.5 is selected from:
N-{(R)-.alpha.-[N-(2-(S)-3-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoy-
l]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)ca-
rbamoyl]-4-hydroxybenzyl}carbamoylmethoxy;
N-((R/S)-.alpha.-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2--
yl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy;
N-[(R)-.alpha.-(N-{2-(S)[N-(carbamoylmethyl)carbamoyl]pyrrolidin-1-ylcarb-
onylmethyl}carbamoyl)benzyl]carbamoylmethoxy;
N-((R)-.alpha.-{N-[2-(3,4,5-trihydroxyphenyl)ethyl]carbamoyl}benzyl)carba-
moylmethoxy; and
N-{(R)-.alpha.-[N-(2-(R)-3-(S)-4-(S)-5-R)-3,4,5,6-tetrahydroxytetrahyropy-
ran-2-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy.
Therefore in a further aspect of the invention there is provided a
compound of formula (I) wherein:
R.sup.v is selected from hydrogen;
R.sup.1 and R.sup.2 are both C.sub.1-6alkyl;
R.sup.x and R.sup.y are both hydrogen;
v is 0;
R.sup.3 and R.sup.6 are both hydrogen;
R.sup.5 is a group of formula (IA) and R.sup.4 is
C.sub.1-6alkylS(O).sub.a wherein a is 0;
X is --O--;
Ring A is aryl; wherein Ring A is optionally substituted on carbon
by one or more substituents selected from R.sup.18; wherein
R.sup.18 is hydroxy;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
R.sup.10 is a group of formula (IB);
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen or
C.sub.1-10alkyl;
R.sup.14 is selected from C.sub.1-10alkyl or
carbocyclylC.sub.1-10alkyl; wherein R.sup.14 may be optionally
substituted on carbon by one or more substituents selected from
R.sup.29; wherein R.sup.29 is hydroxy, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof.
Therefore in a further aspect of the invention there is provided a
compound of formula (I) wherein:
R.sup.v is selected from hydrogen;
R.sup.1 and R.sup.2 are both C.sub.1-6allyl;
R.sup.x and R.sup.y are both hydrogen;
v is 0;
R.sup.3 and R.sup.6 are both hydrogen;
R.sup.5 is a group of formula (IA) and R.sup.4 is
C.sub.1-6alkylS(O).sub.a wherein a is 0;
X is --O--;
Ring A is aryl; wherein Ring A is optionally substituted on carbon
by one or more substituents selected from R.sup.18;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
R.sup.10 is a group of formula (IB) (as depicted above):
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen or
C.sub.1-10alkyl;
R.sup.14 is selected from C.sub.1-10alkyl,
carbocyclylC.sub.1-10alkyl and heterocyclyl; wherein R.sup.14 may
be optionally substituted on carbon by one or more substituents
selected from R.sup.29; or R.sup.14 is a group of formula (IC) (as
depicted above);
R.sup.15 and R.sup.16 together with the nitrogen to which they are
attached form a heterocyclyl; wherein said heterocyclyl may be
optionally substituted on carbon by one or more R.sup.37;
n is 1;
R.sup.18, R.sup.29 and R.sup.37 are independently selected from
hydroxy and N--(C.sub.1-10alkyl)carbamoyl; wherein R.sup.18,
R.sup.29 and R.sup.37 maybe independently optionally substituted on
carbon by one or more R.sup.34; and
R.sup.34 is carbamoyl;
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug thereof.
Therefore in another aspect of the invention there is provided a
compound of formula (I) wherein:
R.sup.v is selected from hydrogen;
R.sup.1 and R.sup.2 are both butyl;
R.sup.x and R.sup.y are both hydrogen;:
v is 0;
R.sup.3 and R.sup.6 are both hydrogen;
R.sup.5 is a group of formula (IA) and R.sup.4 is methylthio;
X is --O--;
Ring A is phenyl or 4-hydroxyphenyl;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
R.sup.10 is a group of formula (IB);
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are both hydrogen or one of R.sup.12 and
R.sup.13 is hydrogen and the other is methyl;
R.sup.14 is selected from 1,2,3,4,5-pentahydroxypentyl or
3,4-dihydroxybenzyl;
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug thereof.
Therefore in another aspect of the invention there is provided a
compound of formula (I) wherein:
R.sup.v is selected from hydrogen;
R.sup.1 and R.sup.2 are both butyl;
R.sup.x and R.sup.y are both hydrogen;
v is 0;
R.sup.3 and R.sup.6 are both hydrogen;
R.sup.5 is a group of formula (IA) and R.sup.4 is methylthio;
X is --O--;
Ring A is phenyl; wherein Ring A is optionally substituted on
carbon by one or more substituents selected from R.sup.18;
R.sup.7 is hydrogen;
R.sup.8 is hydrogen;
R.sup.9 is hydrogen;
R.sup.10 is a group of formula (IB) (as depicted above):
R.sup.11 is hydrogen;
R.sup.12 and R.sup.13 are independently selected from hydrogen or
methyl;
R.sup.14 is selected from pentyl, benzyl and tetrahydropyran;
wherein R.sup.14 may be optionally substituted on carbon by one or
more substituents selected from R.sup.29; or R.sup.14 is a group of
formula (IC) (as depicted above);
R.sup.15 and R.sup.16 together with the nitrogen to which they are
attached form pyrrolidinyl;
wherein said pyrrolidinyl may be optionally substituted on carbon
by one or more R.sup.37;
n is 1;
R.sup.18, R.sup.29 and R.sup.37 are independently selected from
hydroxy and N-methylcarbamoyl;
wherein R.sup.18, R.sup.29 and R.sup.37 may be independently
optionally substituted on carbon by one or more R.sup.34; and
R.sup.34 is carbamoyl;
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug thereof.
Therefore in another aspect of the invention there is provided a
compound of formula (I) wherein:
R.sup.v is selected from hydrogen;
R.sup.1 and R.sup.2 are both butyl;
R.sup.x and R.sup.y are both hydrogen;
v is 0;
R.sup.3 and R.sup.6 are both hydrogen;
R.sup.4 is methylthio; and
R.sup.5 is selected from:
N-{(R)-.alpha.-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)ca-
rbamoyl]benzyl}carbamoylmethoxy;
N-{(R)-.alpha.-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)ca-
rbamoyl]-4-hydroxybenzyl}carbamoylmethoxy;
N-((R/S)-.alpha.-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2--
yl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy;
N-[(R)-.alpha.-(N-{2-(S)-[N-(carbamoylmethyl)carbamoyl]pyrrolidin-1-ylcar-
bonylmethyl}carbamoyl)benzyl]carbamoylmethoxy;
N-((R)-.alpha.-{N-[2-3,4,5-trihydroxyphenyl)ethyl]carbamoyl}benzyl)carbam-
oylmethoxy; and
N-{(R)-.alpha.-[N-(2-(R)-3-(S)-4-(S)-5-(R)-3,4,5,6-tetrahydroxytetrahydro-
pyran-2-ylmethyl)carbamoyl]benzyl}carbamoylmethoxy; or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
In another aspect of the invention, preferred compounds of the
invention are any one of the examples or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof.
Preferred aspects of the invention are those which relate to the
compound of formula (I) or a pharmaceutically acceptable salt
thereof.
Another aspect of the present invention provides a process for
preparing a compound of formula (I) or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof which process (wherein variable groups are, unless
otherwise specified, as defined in formula (I)) comprises of:
Process 1): for compounds of formula (I) wherein X is
--O--,--NR.sup.a or --S--; reacting a compound of formula (IIa) or
(IIb):
##STR00009## with a compound of formula (III):
##STR00010## wherein L is a displaceable group; Process 2):
reacting an acid of formula (IVa) or (IVb):
##STR00011## or an activated derivative thereof, with an amine of
formula (V):
##STR00012## Process 3): for compounds of formula (I) wherein
R.sup.10 is a group of formula (IB); reacting a compound of formula
(VIa):
##STR00013## or (VIb):
##STR00014## with an amine of formula (VII):
##STR00015##
Process 4) for compounds of formula (I) wherein one of R.sup.4 and
R.sup.5 are independently selected from C.sub.1-6alkylthio
optionally substituted on carbon by one or more R.sup.17; reacting
a compound of formula (VIIIa) or (VIIIb):
##STR00016## wherein L is a displaceable group; with a thiol of
formula (IX): R.sup.m--H (IX) wherein R.sup.m is C.sub.1-6alkylthio
optionally substituted on carbon by one or more R.sup.17; or
Process 5): for compounds of formula (I) wherein R.sup.14 is a
group of formula (IC); reacting a compound of formula (Xa):
##STR00017## or (Xb):
##STR00018## with an amine of formula (XI):
##STR00019## and thereafter if necessary or desirable: i)
converting a compound of the formula (I) into another compound of
the formula (I); and/or ii) removing any protecting groups; and/or
ii) forming a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug.
L is a displaceable group, suitable values for L are for example, a
halogeno or sulphonyloxy group, for example a chloro, bromo,
methanesulphonyloxy or toluene-4-sulphonyloxy group.
Specific reaction conditions for the above reactions are as
follows.
The bicyclic ring systems of the present invention may be assembled
according the following scheme. The skilled person will appreciate
to make any of the above identified intermediates the value of
R.sup.4 or R.sup.5 in the following schemes would be replaced with
the appropriate group. For example, to synthesis a compound of
formula (IIa) R.sup.4 would be HX in the following scheme.
##STR00020## ##STR00021##
FGI is functional interconversion of the Br into other values of
R.sup.4 using procedures known to the skilled person.
Compounds of formula (A) and (D) are commercially available, or
they are known in the literature, or they may be prepared by
standard processes known in the art
Process 1): Compounds of formula (IIa) or (IIb) may be reacted with
compounds of formula (III) in the presence of a base for example an
inorganic base such as sodium carbonate, or an organic base such as
Hunigs base, in the presence of a suitable solvent such as
acetonitrile, dichloromethane or tetrahydrofuran at a temperature
in the range of 0.degree. C. to reflux, preferably at or near
reflux.
Compounds of formula (III) are commercially available compounds, or
they are known in the literature, or they are prepared by standard
processes known in the art Process 2) process 3) and Process 5):
Acids and amines may be coupled together in the presence of a
suitable coupling reagent. Standard peptide coupling reagents known
in the art can be employed as suitable coupling reagents, or for
example carbonyldiimidazole and dicyclohexyl-carbodiimide,
optionally in the presence of a catalyst such as
dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the
presence of a base for example triethylamine, pyridine, or
2,6-di-alkyl-pyridines such as 2,6-lutidine or
2,6-di-tert-butylpyridine. Suitable solvents include
dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and
dimethylformamide. The coupling reaction may conveniently be
performed at a temperature in the range of -40 to 40.degree. C.
Suitable activated acid derivatives include acid halides, for
example acid chlorides, and active esters, for example
pentafluorophenyl esters. The reaction of these types of compounds
with amines is well known in the art, for example they may be
reacted in the presence of a base, such as those described above,
and in a suitable solvent, such as those described above. The
reaction may conveniently be performed at a temperature in the
range of -40 to 40.degree. C.
Compounds of formula (IVa) or (IVb) wherein
X.dbd.--O--,--NR.sup.a,--S-- may be prepared according to Scheme
2:
##STR00022##
Wherein L in (VIIa) and (VIIb) is a displaceable group e.g. bromo,
chloro, fluoro, mesyl or tosyl and wherein X is --O--,--S--,
NR.sup.a (optionally for --SO-- and --SO.sub.2-- followed by the
oxidation step of Process 1).
Compounds of formula (IVa) and (IVb) where X is --SO-- or
--SO.sub.2-- may be prepared by oxidising the resulting compounds
of formula (IVa) and (IVb) from Scheme 2 where X is --S--.
Compounds of formula (Va) or (Vb) wherein X is --CH.sub.2-- may be
prepared according to Scheme 3.
##STR00023## Process 4): Compounds of formula (VIIIa) and (VIIIb)
may be reacted with thiols of formula (VIII) in the presence of
base, for example an inorganic base such as sodium carbonate or an
organic base such as Hunigs base, in the presence of a suitable
solvent such as DMF or THF at a temperature in the range of
0.degree. C. to reflux.
Compounds of formula (VIIIa) and (VIIIb) may be prepared by any of
the procedures above for the preparation of compounds of formula
(I), but wherein one of R.sup.4 and R.sup.5 is L.
Other starting materials are commercially available compounds, or
they are known in the literature, or they are prepared by standard
processes known in the art.
It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halogeno group. Particular examples of
modifications include the reduction of a nitro group to an amino
group by for example, catalytic hydrogenation with a nickel
catalyst or treatment with iron in the presence of hydrochloric
acid with heating; oxidation of alkylthio to alkylsulphinyl or
alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned
herein it may be necessary/desirable to protect any sensitive
groups in the compounds. The instances where protection is
necessary or desirable and suitable methods for protection are
known to those skilled in the art. Conventional protecting groups
may be used in accordance with standard practice (for illustration
see T. W. Green, Protective Groups in Organic Synthesis, John Wiley
and Sons, 1999). Thus, if reactants include groups such as amino,
carboxy or hydroxy it may be desirable to protect the group in some
of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is,
for example, an acyl group, for example an alkanoyl group such as
acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a t-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulphuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium-on-carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an
acyl group, for example an alkanoyl group such as acetyl, an aroyl
group, for example benzoyl, or an arylmethyl group, for example
benzyl. The deprotection conditions for the above protecting groups
will necessarily vary with the choice of protecting group. Thus,
for example, an acyl group such as an alkanoyl or an aroyl group
may be removed, for example, by hydrolysis with a suitable base
such as an alkali metal hydroxide, for example lithium or sodium
hydroxide. Alternatively an arylmethyl group such as a benzyl group
may be removed, for example, by hydrogenation over a catalyst such
as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an
esterifying group, for example a methyl or an ethyl group which may
be removed, for example, by hydrolysis with a base such as sodium
hydroxide, or for example a t-butyl group which may be removed, for
example, by treatment with an acid, for example an organic acid
such as trifluoroacetic acid, or for example a benzyl group which
may be removed, for example, by hydrogenation over a catalyst such
as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the
synthesis using conventional techniques well known in the chemical
art.
As stated hereinbefore the compounds defined in the present
invention possess IBAT inhibitory activity. These properties may be
assessed, for example, using an in vitro test assay for studying
the effect on bile acid uptake in IBAT-transfected cells (Smith L.,
Price-Jones M. J., Hugnes K. T. and Jones N. R. A.; J Biomolecular
Screening, 3, 227 230) or in vivo by studying the effect on
radiolabelled bile acid absorption in mice/rats (Lewis M. C.,
Brieaddy L. E. and Root C., J., J Lip Res 1995, 36, 1098 1105).
According to a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of formula
(I), or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof, as defined hereinbefore in
association with a pharmaceutically-acceptable diluent or
carrier.
The composition may be in a form suitable for oral administration,
for example as a tablet or capsule, for parenteral injection
(including intravenous, subcutaneous, intramuscular, intravascular
or infusion) as a sterile solution, suspension or emulsion, for
topical administration as an ointment or cream or for rectal
administration as a suppository.
In general the above compositions may be prepared in a conventional
manner using conventional excipients.
The compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, will normally
be administered to a warm-blooded animal at a unit dose within the
range 5 5000 mg per square meter body area of the animal, i.e.
approximately 0.1 100 mg/kg or 0.01 50 mg/kg, and this normally
provides a therapeutically-effective dose. A unit dose form such as
a tablet or capsule will usually contain, for example 1 250 mg of
active ingredient. Preferably a daily dose in the range of 1 50
mg/kg is employed. In another aspect a daily dose in the rage of
0.02 20 mg/kg is employed. However the daily dose will necessarily
be varied depending upon the host treated, the particular route of
administration, and the severity of the illness being treated.
Accordingly the optimum dosage may be determined by the
practitioner who is treating any particular patient.
According to a further aspect of the present invention there is
provided a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, as defined hereinbefore for use in a method of
prophylactic or therapeutic treatment of a warm-blooded animal,
such as man.
We have found that the compounds defined in the present invention,
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug thereof, are effective IBAT inhibitors, and
accordingly have value in the treatment of disease states
associated with hyperlipidaemic conditions.
Thus according to this aspect of the invention there is provided a
compound of the formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, as defined
hereinbefore for use as a medicament.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, as defined hereinbefore in the manufacture of a medicament
for use in the production of an IBAT inhibitory effect in a
warm-blooded animal, such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, as defined hereinbefore in the manufacture of a medicament
for use in the treatment of hyperlipidaemic conditions in a
warm-blooded animal, such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, as defined hereinbefore in the manufacture of a medicament
for use in the treatment of hyperlipidaemic conditions and
disorders such as hyperlipidaemia, hypertrigliceridemia,
hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia
(high VLDL), hyperchylomicronemia, hypolipoproteinemia,
hypercholesterolemia, hyperlipoproteinemia and
hypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such
as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, as defined hereinbefore in the manufacture of a medicament
for use in the treatment of different clinical conditions such as
atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic
conditions, vascular dysfunction, endothelial dysfunction, heart
failure, coronary heart diseases, cardiovascular diseases,
myocardial infarction, angina pectoris, peripheral vascular
diseases, inflammation of cardiovascular tissues such as heart,
valves, vasculature, arteries and veins, aneurisms, stenosis,
restenosis, vascular plaques, vascular fatty streaks, leukocytes,
monocytes and/or macrophage infiltration, intimal thickening,
medial thinning, infectious and surgical trauma and vascular
thrombosis, stroke and transient ischaemic attacks in a
warm-blooded animal, such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, as defined hereinbefore in the manufacture of a medicament
for use in the treatment of atherosclerosis, coronary heart
diseases, myocardial infarction, angina pectoris, peripheral
vascular diseases, stroke and transient ischaemic attacks in a
warm-blooded animal, such as man.
According to a further feature of this aspect of the invention
there is provided a method for producing an IBAT inhibitory effect
in a warm-blooded animal, such as man, in need of such treatment
which comprises administering to said animal an effective amount of
a compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof.
According to a further feature of this aspect of the invention
there is provided a method of treating hyperlipidemic conditions in
a warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof.
According to a further feature of this aspect of the invention
there is provided a method of treating dyslipidemic conditions and
disorders such as hyperlipidaemia, hypertrigliceridemia,
hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia
(high VLDL), hyperchylomicronemia, hypolipoproteinemia,
hypercholesterolemia, hyperlipoproteinemia and
hypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such
as man, in need of such treatment which comprises administering to
said animal an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
According to a further feature of this aspect of the invention
there is provided a method of treating different clinical
conditions such as atherosclerosis, arteriosclerosis, arrhythmia,
hyper-thrombotic conditions, vascular dysfunction, endothelial
dysfunction, heart failure, coronary heart diseases, cardiovascular
diseases, myocardial infarction, angina pectoris, peripheral
vascular diseases, inflammation of cardiovascular tissues such as
heart, valves, vasculature, arteries and veins, aneurisms,
stenosis, restenosis, vascular plaques, vascular fatty streaks,
leukocyte, monocytes and/or macrophage infiltrate, intimital
thickening, medial thinning, infectious and surgical trauma and
vascular thrombosis, stroke and transient ischaemic attacks in need
of such treatment which comprises administering to said animal an
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
According to a further feature of this aspect of the invention
there is provided a method of treating atherosclerosis, coronary
heart diseases, myocardial infarction, angina pectoris, peripheral
vascular diseases, stroke and transient ischaemic attacks in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof.
There is evidence that an IBAT inhibitor might potentially be
useful in the treatment and/or prevention of gallstones. According
to a further feature of this aspect of the invention there is
provided a method of treating and/or preventing gallstones in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof.
The size of the dose required for the therapeutic or prophylactic
treatment will necessarily be vaned depending on the host treated,
the route of administration and the severity of the illness being
treated. A unit dose in the range, for example, 0.02 50 mg/kg,
preferably 0.1 100 mg/kg is envisaged.
The IBAT inhibitory activity defined hereinbefore may be applied as
a sole therapy or may involve, in addition to a compound of the
invention, one or more other substances and/or treatments. Such
conjoint tent may be achieved by way of the simultaneous,
sequential or separate administration of the individual components
of the treatment. According to this aspect of the invention there
is provided a pharmaceutical product comprising a compound of the
formula (I), or a pharmaceutically acceptable salt, solvate,
solvate of such a salt or a prodrug thereof, as defined
hereinbefore and an additional IBAT inhibitory substance as defined
hereinbefore and an additional hypolipidaemic agent for the
conjoint treatment of hyperlipidaemia.
In another aspect of the invention, the compound of formula (I), or
a pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, may be administered in association with an
HMG Co-A reductase inhibitor, or pharmaceutically acceptable salts,
solvates, solvates of such salts or prodrugs thereof. Suitable HMG
Co-A reductase inhibitors, pharmaceutically acceptable salts,
solvates, solvates of such salts or prodrugs thereof are statins
well known in the art. Particular statins are fluvastatin,
lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin,
bervastatin, dalvastatin, mevastatin and
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyr-
imidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin),
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a plug thereof. A particular statin is atorvastatin, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof. A more particular statin is atorvastatin
calcium salt. A further particular statin is
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid
(rosuvastatin), or a pharmaceutically acceptable salt, solvate,
solvate of such a salt or a prodrug thereof. A preferable
particular statin is rosuvastatin calcium salt.
In an additional aspect of the invention, the compound of formula
(I), or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof may be administered in association
with an HMG Co-A reductase inhibitor, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, and/or a bile acid binder thereby avoiding a possible risk
of excess of bile acids in colon caused by the inhibition of the
ileal bile acid transport system. An excess of bile acids in the
visceral contents may cause diarrhoea. Thus, the present invention
also provides a treatment of a possible side effect such as
diarrhoea in patients during therapy comprising the compound of
formula (I), or a pharmaceutically acceptable salt, solvate,
solvate of such a salt or a prodrug thereof.
An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable
salt, solvate, solvate of such a salt or a prodrug thereof will by
its action decrease the endogenous cholesterol available for the
bile acid synthesis and have an additive effect in combination with
the compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof on lipid
lowering.
Suitable bile acid binders for such a combination therapy are
resins, such as cholestyramine and cholestipol. One advantage is
that the dose of bile acid binder might be kept lower than the
therapeutic dose for treatment of cholesterolaemia in single
treatment comprising solely a bile acid binder. By a low dose of
bile acid binder any possible side effects caused by poor tolerance
of the patient to the therapeutic dose could also be avoided.
Therefore in an additional feature of the invention, there is
provided a method for producing an IBAT inhibitory effect in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of an HMG Co-A reductase inhibitor, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
Therefore in an additional feature of the invention, there is
provided a method for producing an IBAT inhibitory effect in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with a bile
acid binder.
Therefore in an additional feature of the invention, there is
provided a method for producing an IBAT inhibitory effect in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of an HMG Co-A reductase inhibitor, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, in simultaneous, sequential or separate
administration with a bile acid binder.
Therefore in an additional feature of the invention, there is
provided a method of treating hyperlipidemic conditions in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of an HMG Co-A reductase inhibitor, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
Therefore in an additional feature of the invention, there is
provided a method of treating hyperlipidemic conditions in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of a bile acid binder.
Therefore in an additional feature of the invention, there is
provided a method of treating hyperlipidemic conditions in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of an HMG Co-A reductase inhibitor, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, in simultaneous, sequential or separate
administration with a bile acid binder.
According to a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of formula
(I), or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof, and an HMG Co-A reductase
inhibitor, or a pharmaceutically acceptable salt, solvate, solvate
of such a salt or a prodrug thereof, in association with a
pharmaceutically acceptable diluent or carrier.
According to a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of formula
(I), or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof, and a bile acid binder, in
association with a pharmaceutically acceptable diluent or
carrier.
According to a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of formula
(I), or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof, and an HMG Co-A reductase
inhibitor, or a pharmaceutically acceptable salt, solvate, solvate
of such a salt or a prodrug thereof, and a bile acid binder in
association with a pharmaceutically acceptable diluent or
carrier.
According to a further aspect of the present invention there is
provided a kit comprising a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
According to a further aspect of the present invention there is
provided a kit comprising a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, and a bile acid binder.
According to a further aspect of the present invention there is
provided a kit comprising a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, and an HMG Co-A reductase inhibitor, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof and a bile acid binder.
According to a further aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, in a first unit dosage form; b) an HMG Co-A
reductase inhibitor, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof; in a second
unit dosage form; and c) container means for containing said first
and second dosage forms.
According to a further aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, in a first unit dosage form; b) a bile acid
binder; in a second unit dosage form; and c) container means for
containing said first and second dosage forms.
According to a further aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, in a first unit dosage form; b) an, HMG Co-A
reductase inhibitor, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof; in a second
unit dosage form; c) a bile acid binder, in a third unit dosage
form; and d) container means for containing said first, second and
third dosage forms.
According to a further aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, together with a pharmaceutically acceptable
diluent or carrier, in a first unit dosage form; b) an HMG Co-A
reductase inhibitor, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in a second
unit dosage form; and c) container means for containing said first
and second dosage forms.
According to a Per aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, together with a pharmaceutically acceptable
diluent or carrier, in a first unit dosage form; b) a bile acid
binder, in a second unit dosage form; and c) container means for
containing said first and second dosage forms.
According to a further aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, together with a pharmaceutically acceptable
diluent or carrier, in a first unit dosage form; b) an HMG Co-A
reductase inhibitor, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in a second
unit dosage form; and c) a bile acid binder; in a third unit dosage
form; and d) container means for containing said first, second and
third dosage forms.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, in the manufacture of a medicament for use in the
production of an IBAT inhibitory effect in a warm-blooded animal,
such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, and a bile acid binder, in the manufacture of a medicament
for use in the production of an IBAT inhibitory effect in a
warm-blooded animal, such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, and an HMG Co-A reductase inhibitor, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, and a bile acid binder, in the manufacture of a medicament
for use in the production of an IBAT inhibitory effect in a
warm-blooded animal, such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, an HMG Co-A reductase inhibitor, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, in the manufacture of a medicament for use in the
treatment of hyperlipidaemic conditions in a warm-blooded animal,
such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, a bile acid binder, in the manufacture of a medicament for
use in the treatment of hyperlipidaemic conditions in a
warm-blooded animal, such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, an HMG Co-A reductase inhibitor, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, and a bile acid binder, in the manufacture of a medicament
for use in the treatment of hyperlipidaemic conditions in a
warm-blooded animal, such as man.
According to a further aspect of the present invention there is
provided a combination treatment comprising the administration of
an effective amount of a compound of the formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, optionally together with a pharmaceutically
acceptable diluent or carrier, with the simultaneous, sequential or
separate administration of an effective amount of an HMG Co-A
reductase inhibitor, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, optionally
together with a pharmaceutically acceptable diluent or carrier to a
warm-blooded animal, such as man in need of such therapeutic
treatment.
According to a further aspect of the present invention there is
provided a combination treatment comprising the administration of
an effective amount of a compound of the formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, optionally together with a pharmaceutically
acceptable diluent or carrier, with the simultaneous, sequential or
separate administration of an effective amount of a bile acid
binder, optionally together with a pharmaceutically acceptable
diluent or carrier to a warm-blooded animal, such as man in need of
such therapeutic treatment.
According to a further aspect of the present invention there is
provided a combination treatment comprising the administration of
an effective amount of a compound of the formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, optionally together with a pharmaceutically
acceptable diluent or carrier, with the simultaneous, sequential or
separate administration of an effective amount of an HMG Co-A
reductase inhibitor, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, optionally
together with a pharmaceutically acceptable excipient, with the
simultaneous, sequential or separate administration of an effective
amount of a bile acid binder, optionally together with a
pharmaceutically acceptable diluent or carrier to a warm-blooded
animal, such as man in need of such therapeutic treatment.
According to an additional further aspect of the present invention
there is provided a combination treatment comprising the
administration of an effective amount of a compound of the formula
(I), or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof, optionally together with a
pharmaceutically acceptable diluent or carrier, with the
simultaneous, sequential or separate administration one or more of
the following agents selected from: a CETP (cholesteryl ester
transfer protein) inhibitor, for example those referenced and
described in WO 00/38725 page 7 line 22--page 10, line 17 which are
incorporated herein by reference;, a cholesterol absorption
antagonist for example azetidinones such as SCH 58235 and those
described in U.S. Pat. No. 5,767,115 which are incorporated herein
by reference; a MTP (microsomal transfer protein) inhibitor for
example those described in Science, 282, 751 54, 1998 which are
incorporated herein by reference; a fabric acid derivative; for
example clofibrate, gemfibrozil, fenofibrate, ciprofibrate and
bezafibrate; a nicotinic acid derivative, for example, nicotinic
acid (niacin), acipimox and niceritrol; a phytosterol compound for
example stanols; probucol; an anti-obesity compound for example
orlistat (EP 129,748) and sibutramine (GB 2,184,122 and U.S. Pat.
No. 4,929,629); an antihypertensive compound for example an
angiotensin converting enzyme (ACE) inhibitor, an angiotensin II
receptor antagonist, an andrenergic blocker, an alpha andrenergic
blocker, a beta andrenergic blocker, a mixed alpha/beta andrenergic
blocker, an andrenergic stimulant, calcium channel blocker, a
diuretic or a vasodilator, insulin; sulphonylureas including
glibenclamide, tolbutamide; metformin; and/or acarbose; or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, optionally together with a pharmaceutically
acceptable diluent or carrier to a warm-blooded animal, such as man
in need of such therapeutic treatment.
Particular ACE inhibitors or pharmaceutically acceptable salts,
solvates, solvate of such salts or a prodrugs thereof, including
active metabolites, which can be used in combination with a
compound of formula (I) include but are not limited to, the
following compounds: alacepril, alatriopril, altiopril calcium,
ancovenin, benazepril, benazepril hydrochloride, benazeprilat,
benzoylcaptopril, captopril, captopril-cysteine,
captopril-glutathione, ceranapril, ceranopril, ceronapril,
cilazapril, cilazaprilat, delapril, delapril-acid, enalapril,
enalaprilat, enapril, epicaptopril, foroxyniithine, fosfenopril,
fosenopril, fosenopril sodium, fosinopril, fosinopril sodium,
fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril,
imidapril, indolapril, indolaprilat, libenzapril, lisinopril,
lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat,
moveltipril, muracein A, muracein B, muracein C, pentopril,
perindopril, perindoprilat, pivalopril, pivopril, quinapril,
quinapril hydrochloride, quinaprilat, ramipril, ramiprilat,
spirapri, spirapril hydrochloride, spiraprilat, spiropril,
spiropril hydrochloride, temocapril, temocapril hydrochloride,
teprotide, trandolapril, trandolaprilat, utibapril, zabicipril,
zabiciprilat, zofenopril and zofenoprilat. Preferred ACE inhibitors
for use in the present invention are ramipril, ramiprilat,
lisinopril, enalapril and enalaprilat. More preferred ACE
inhibitors for uses in the present invention are ramipril and
ramiprilat.
Preferred angiotensin II antagonists, pharmaceutically acceptable
salts, solvates, solvate of such salts or a prodrugs thereof for
use in combination with a compound of formula (I) include, but are
not limited to, compounds: candesartan, candesartan cilexetil,
losartan, valsartan, irbesartan, tasosartan, telmisartan and
eprosartan. Particularly preferred angiotensin II antagonists or
pharmaceutically acceptable derivatives thereof for use in the
present invention are candesartan and candesartan cilexetil.
In another aspect of the invention, the compound of formula (I), or
a pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, may be administered in association with a
PPAR alpha and/or gamma agonist, or pharmaceutically acceptable
salts, solvates, solvates of such salts or prodrugs thereof.
Suitable PPAR alpha and/or gamma agonists, pharmaceutically
acceptable salts, solvates, solvates of such salts or prodrugs
thereof are well known in the art. These include the compounds
described in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO
99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39, 665,
Expert Opinion on Therapeutic Patents, 10 (5), 623 634 (in
particular the compounds described in the patent applications
listed on page 634) and J Med Chem, 2000, 43, 527 which are all
incorporated herein by reference. Particularly a PPAR alpha and/or
gamma agonist refers to WY-14643, clofibrate, fenofibrate,
bezafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone,
eglitazone, proglitazone, BRL-49634, KRP-297, JTT-501, SB 213068,
GW 1929, GW 7845, GW. 0207, L-796449, L-165041 and GW 2433.
Particularly a PPAR alpha and/or gamma agonist refers to
(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl-
]propanoic acid and pharmaceutically acceptable salts thereof.
Additional suitable PPAR alpha and/or gamma agonists are
NN622/Ragaglitazar and BMS 298585.
Therefore in an additional feature of the invention, there is
provided a method for producing an IBAT inhibitory effect in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of a PPAR alpha and/or gamma agonist, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
Therefore in an additional feature of the invention, there is
provided a method of treating hyperlipidemic conditions in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of a PPAR alpha and/or gamma agonist, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
According to a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of formula
(I), or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof, and a PPAR alpha and/or gamma
agonist, or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof, in association with a
pharmaceutically acceptable diluent or carrier.
According to a further aspect of the present invention there is
provided a kit comprising a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, and a PPAR alpha and/or gamma agonist, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
According to a further aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, in a first unit dosage form; b) a PPAR alpha
and/or gamma agonist, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof; in a second
unit dosage form; and c) container means for containing said first
and second dosage forms.
According to a further aspect of the present invention there is
provided a kit comprising: a) a compound of formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, together with a pharmaceutically acceptable
diluent or carrier, in a first unit dosage form; b) a PPAR alpha
and/or gamma agonist, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in a second
unit dosage form; and c) container means for containing said first
and second dosage forms.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, and a PPAR alpha and/or gamma agonist, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, in the manufacture of a medicament for use in
the production of an IBAT inhibitory effect in a warm-blooded
animal, such as man.
According to another feature of the invention there is provided the
use of a compound of the formula (I), or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, a PPAR alpha and/or gamma agonist, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, in the manufacture of a medicament for use in the
treatment of hyperlipidaemic conditions in a warn-blooded animal,
such as man.
According to a further aspect of the present invention there is
provided a combination treatment comprising the administration of
an effective amount of a compound of the formula (I), or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, optionally together with a pharmaceutically
acceptable diluent or carrier, with the simultaneous, sequential or
separate administration of an effective amount of a PPAR alpha
and/or gamma agonist, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, optionally
together with a pharmaceutically acceptable diluent or carrier to a
warm-blooded animal, such as man in need of such therapeutic
treatment.
In addition to their use in therapeutic medicine, the compounds of
formula (I), or a pharmaceutically acceptable salt, solvate,
solvate of such a salt or a prodrug thereof, are also useful as
pharmacological tools in the development and standardisation of in
vitro and in vivo test systems for the evaluation of the effects of
inhibitors of IBAT in laboratory animals such as cats, dogs,
rabbits, monkeys, rats and mice, as part of the search for new
therapeutic agents.
Many of the intermediates described herein are novel and are thus
provided as a further feature of the invention.
In the above other pharmaceutical composition, process, method, use
and medicament manufacture features, the alternative and particular
embodiments of the compounds of the invention described herein also
apply.
EXAMPLES
The invention will now be illustrated in the following non limiting
examples, in which standard techniques known to the skilled chemist
and techniques analogous to those described in these examples may
be used where appropriate, and in which, unless otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo
and work up procedures were carried out after removal of residual
solids such as drying agents by filtration; (ii) all reactions were
carried out under an inert atmosphere at ambient temperature,
typically in the range 18 25.degree. C., with solvents of HPLC
grade under anhydrous conditions, unless otherwise stated; (iii)
column chromatography (by the flash procedure) was performed on
Silica gel 40 63 .mu.m (Merck); (iv) yields are given for
illustration only and are not necessarily the maximum attainable;
(v) the structures of the end products of the formula (I) were
generally confirmed by nuclear (generally proton) magnetic
resonance (NMR) and mass spectral techniques; magnetic resonance
chemical shift values were measured in deuterated CD.sub.30OD
(unless otherwise stated) on the delta scale (ppm downfield from
tetramethylsilane); proton data is quoted unless otherwise stated;
spectra were recorded on a Varian Mercury-300 MHz, Varian Unity
plus-400 MHz, Varian Unity plus-600 MHz or on Varian Inova-500 MHz
spectrometer, and peak multiplicities are shown as follows: s,
singlet; d, doublet; dd, double doublet; t, triplet; tt, triple
triplet; q, quartet; tq, triple quartet; m, multiplet; br, broad;
LCMS were recorded on a Waters ZMD, LC column xTerra MS
C.sub.8(Waters), detection with a HP 1100 MS-detector diode array
equipped; mass spectra (MS) (loop) were recorded on VG Platform II
(Fisons Instruments) with a HP-1100 MS-detector diode array
equipped; unless otherwise stated the mass ion quoted is
(MH.sup.+); (vi) unless further details are specified in the text,
analytical high performance liquid chromatography (HPLC) was
performed on Prep LC 2000 (Waters), Kromasil C.sub.8, 7 .mu.m,
(Akzo Nobel); MeCN and de-ionised water 100 mM ammonium acetate as
mobile phases, with suitable composition; (vii) intermediates were
not generally fully characterised and purity was assessed by thin
layer chromatography (TLC), HPLC, infra-red (IR), MS or NMR
analysis; (viii) where solutions were dried sodium sulphate was the
drying agent; (ix) where an "ISOLUTE" column is referred to, this
means a column containing 2 g of silica, the silica being contained
in a 6 ml disposable syringe and supported by a porous disc of 54
.ANG. pore size, obtained from International Sorbent Technology
under the name "ISOLUTE"; "ISOLUTE" is a registered trade mark; (x)
the following abbreviations may be used hereinbefore or
hereinafter:--
DCM dichloromethane;
DMF N,N-dimethylformamide;
TBTU o-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate;
EtOAc ethyl acetate;
MeCN acetonitrile;
TFA trifluoroacetic acid;
HATU o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate; and
DIPEA di-isopropylethyiamine.
Example 1
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(S)-3--
(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmeth-
oxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazenine
A solution of
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N--((R)-.alpha.-carboxyben-
zyl)carbamoylmethoxyl]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
(Method 1; 0.055 g, 0.086 mmol), D-glucitol, 1-amino-1-deoxy-(0.017
g, 0.094 mmol) and N-methylmorpholine (0.028 ml, 0.254 mmol) in DMF
(4 ml) was stirred for 10 min, after which TBTU (0.033 g, 0.103
mmol) was added. After 18 h the solution was diluted with toluene
and then concentrated. The residue was purified by preparative HPLC
using a gradient of 40 60% MeCN in 0.1M ammonium acetate buffer as
eluent The title compound was obtained in 0.041 g (59%) as a white
solid. NMR (400 MHz, DMSO-d.sub.6): 0.60 0.85 (6H, m), 0.85 1.65
(12H, m), 2.10 (3H, s), 2.95 3.05 (1H, m), 3.20 3.70 (17H
(7CH+H2O), m), 3.85 (2H, bs), 4.20 4.45 (4H, m), 4.60 4.80 (3H, m),
5.55 (1H, d), 6.60 (1H, s), 6.90 7.50 (12H, m), 8.30 8.55 (2H, m);
m/z 803.3429.
Example 2
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(S)-3--
(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}car-
bamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-carboxy-4-h-
ydroxybenzyl)
carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
(Method 5; 45.5 mg, 0.070 mmol) was dissolved in 3 ml DMF.
N-Methylmorpholine (16 .mu.l, 14 mmol) and D-glucamine (16 mg,
0.084 mmol) were added and the mixture was stirred for 20 min. TBTU
(27 mg, 0.084 mmol) was added and the reaction mixture was stirred
overnight. To obtain complete transformation of the starting
material, D-glucamine (13.5 mg, 0.079 mmol), N-methylmorpholine (8
.mu.l, 0.070 mmol), catalytic amount of tetrabutylammonium bromide
and TBTU (3.times.5 mg in portions, 0.04 mmol) were added
successively. The reaction mixture was concentrated and purified
using preparative HPLC on a C8 column (50.times.250 mm) with a
gradient (20/80 to 50/50) of MeCN/0.1M ammonium acetate buffer as
eluent. The product fraction was concentrated to remove the MeCN
and then lyophilized to yield the title compound in 31 mg (53%
yield). NMR (400 MHz): 0.8 (t, 6H), 1.0 1.2 (m, 6H), 1.25 1.4 (m,
2H), 1.4 1.5 (m, 2H), 1.55 1.7 (m, 2H), 2.1 (s, 3H), 3.15 3.25 (m,
2H), 3.45 3.7 (m, 5H), 3.73 (dd, 1H), 3.8 3.85 (m, 1H), 3.95 (brs,
2H), 4.6 (ABq, 2H), 5.3 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05
(t, 1H) 7.15 7.4 (m, 7H); m/z: 819.
Examples 3 and 4
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-.alpha.-{N-[1-(R)--
2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}benzyl)carbamoy-
lmethoxy]-2,3.4,5-tetrahydro-1,2,5-benzothiadiazepine enantiomer
1
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-.alpha.-{N-[1-(R)--
2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}benzyl)carbamoy-
lmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine enantiomer
2
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-carboxybenz-
yl) carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
(Method 1; 50 mg, 0.078 mmol) and
4-[(1R,2S)-2-amino-1-hydroxypropyl]benzene-1,2-diol (17.9 mg, 0.098
mmol) were dissolved in DCM (1 ml), DMF (2 ml). N-Methylmorpholine
(17.2 .mu.l, 0.156 mmol) and TBTU (45 mg, 0.14 mmol) were added.
The reaction mixture was stirred over night and then evaporated
under reduced pressure. Proton NMR showed a mixture of two
diastereomers due to epimerisation in the phenylglycinresidue. The
two diastereomers was separated by preparative HPLC using an
acetonitrile/ammonium acetate buffer gradient (5/95 to 100/0) as
eluent. The diastereomer that eluted first gave 7 mg (11%) after
lyophilisation. NMR (500 MHz): 0.81 (brt, 6H), 1.0 1.26 (m, 9H),
1.26 1.41 (m, 2H), 1.42 1.53 (m, 2H), 1.57 1.7 (m, 2H), 2.11 (s,
3H), 3.85 4.2 (m, 3H), 4.33 (d, 1H), 4.65 (ABq, 2H), 5.47 (s, 1H),
6.53 (dd, 1H), 6.57 6.63 (m, 2H), 6.73 (d, 1H), 7.07 (brt, 1H),
7.11 7.17 (m, 2H), 7.18 7.38 (m, 8H); m/z 803.9 (M-H).sup.-. The
diastereomer eluted second gave 15 mg (24%) after lyophilisation.
NMR (500 MHz): 0.81 (brt, 6H), 1.0 1.25 (m, 9H), 1.25 1.4 (m, 2H),
1.42 1.52 (m, 2H), 1.57 1.7 (m, 2H), 2.12 (s, 3H), 3.8 4.13 (m,
3H), 4.56 4.74 (m, 3H), 5.47 (s, 1H), 6.61 (brs, 1H), 6.67 6.73 (m,
2H), 6.83 (s, 1H), 7.07 (brt, 1H), 7.15 7.40 (m, 10H); m/z 803.9
(M-).sup.-.
Example 5
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-.alpha.-(N-{2-(S)-[N-
-(carbamoylmethyl)
carbamoyl]pyrrolidin-1-ylcarbonylmethyl}carbamoyl)benzyl]carbamoylmethoxy-
}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-carboxybenz-
yl) carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
(Method 1; 46 mg, 0.070 mmol) was dissolved in DMF (2 ml).
(2S)-1-(aminoacetyl)-N-(carbamoylmethyl)pyrrolidine-2-carboxamide
(25 mg, 0.094 mmol) and N-methylmorpholine (16 .mu.l, 0.145 mmol)
were added. The solution became cloudy and DMF (1 ml) was added.
TBTU (21 mg, 0.084 mmol) was added in two portions over 10 minutes
and the mixture was stirred for 1.5 hours. Formic acid (2 drops)
was added after 2 hours. The mixture was purified using preparative
HPLC on a C8 column (50.times.250 mm). A step gradient from 20 60%
MeCN in 0.1M ammonium acetate buffer was used as eluent. The
product fraction was concentrated and lyophilised to yield 22 mg
(37%). NMR (400 MHz, CD.sub.3OD): 0.79 (t, 6H), 0.98 1.24 (m, 6H),
1.24 1.4 (m, 2H), 1.46 (brt, 2H), 1.55 1.7 (m, 2H),1.85 2.12 (m,
6H), 2.12 2.24 (m, 1H), 3.4 3.66(m, 2H), 3.7 4.15 (m, 6H), 4.31
4.37 (m, 1H), 4.63 (ABq, 2H), 5.61 (s, 1H), 6.58 (s, 1H), 7.04 (t,
1H), 7.20 (brd, 2H), 7.24 7.38 (m, 6H), 7.46 (brd, 2H).
Example 6
1,1-Dioxo-3.3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-{N-[2-(3,4,5-
-trihydroxyphenyl)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahy-
dro-1,2,5-benzothiadiazepine
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-carboxybenz-
yl) carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
(Method 1; 60 mg, 0.094 mmol), 5-(2-aminoethyl)benzene-1,2,3-triol
(25 mg, 0.12 mmol) and N-methylmorpholine (21 .mu.l, 0.188 mmol)
were dissolved in DMF (2 ml). TBTU (38 mg, 0.12 mmol) was added and
the mixture was stirred for 45 minutes. The product was purified by
preparative HPLC using a MeCN/ammonium acetate buffer gradient
(5/95 to 100/0) as eluent to give the title compound 37 mg (50%).
NMR (400 Mz, CD.sub.3OD): 0.79 (t, 6H), 0.95 1.24 (m, 6H), 1.24
1.39 (m, 2H), 1.45 (brt, 2H), 1.54 1.69 (m, 2H), 2.09 (s, 3H), 2.53
(t, 2H), 3.35 (t, 2H), 3.75 4.12 (m, 2H), 4.64 (ABq, 2H), 5.44 (s,
1H), 6.16 (s, 2H), 6.58 (s, 1H), 7.04 (brt; 1H), 7.11 7.45 (m,
10H).
Example 7
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(R)-3--
(S)-4-(S)-5-(R)-3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethyl)carbamoyl]b-
enzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-carboxybenz-
yl) carbamoylmethoxyl]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
(Method 1; 56 mg, 0.088 mmol),
3-(R)-4-(S)-5-(S)-6-(R)-2,3,4,5-tetrahydroxy-6-(aminomethyl)
tetrahydropyran (25.4 mg, 0.12 mmol) and N-methylmorpholine (19
.mu.l, 0.175 mmol) were dissolved in DMF (2 ml) and water (10
drops). TBTU (34 mg, 0.105 mmol) was added and the mixture was
stirred for 2 hours. More TBTU (22 mg) and
3-(R)-4-(S)-5-(S)-6-(R)-2,3,4,5-tetrahydroxy-6-(aminomethyl)tetrahydropyr-
an (5 mg) were added and stirred for a short period. The product
was purified by preparative HPLC using a MeCN/ammonium acetate
buffer gradient (5/95 to 100/0) as eluent to give the title
compound 39 mg (56%). M/z 799.55 (M-H).sup.-.
Preparation of Starting Materials
The starting materials for the Examples above are either
commercially available or are readily prepared by standard methods
from known materials. For example, the following reactions are an
illustration, but not a limitation, of some of the starting
materials used in the above reactions.
Method 1
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-carboxybenzy-
l)
carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-.alpha.-(t-butoxyca-
rbonyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-
e (Method 2; 762 mg, 1.09 mmol) was dissolved in a mixture of TFA
(6.65 ml) and triethylsilane (0.350 ml). The reaction mixture was
stirred for one hour and then evaporated under reduced pressure to
give the title compound in a quantitative yield (714 mg). NMR (500
MHz): 0.8 (brt, 6H), 0.96 1.25 (m, 6H), 1.25 1.4 (m, 2M), 1.42 1.51
(m, 2H), 1.57 1.69 (m, 2H), 2.11 (s, 3H), 3.8 4.15 (m, 2H), 4.66
(ABq, 2H), 5.49 5.53 (m, 1H), 6.61 (s, 1H), 7.06 (t, 1H), 7.18 7.26
(m, 2H), 7.28 7.45 (m, 8H), 8.35 (d, NH); m/z 640.2.
Method 2
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N--[(R)-.alpha.-(t-butoxyca-
rbonyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-
e
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetr-
ahydro-1,2,5-benzothiadiazepine (Method 3; 627 mg, 1.24 mmol) was
dissolved in DCM (25 ml), tert-butyl (2R)-amino(phenyl)acetate (308
mg, 1.48 mmol, 2,6-dimethylpyridine (288 .mu.l, 2.47 mmol) and TBTU
(477 mg, 1.48 mmol) were added. The mixture was stirred for 3.5
hours. The reaction mixture was evaporated under reduced pressure.
The product was purified using an Isolute column (10 g, silica).
The product was eluted with a stepwise gradient using DCM:EtOAc
100:0 then 95:5. Approximately 694 mg pure compound was collected
An additional fraction was purified a second time using an Isolute
column (10 g, silica). The product was eluted with a stepwise
gradient using DCM:EtOAc 100:0, 95:5 then 90:10. The pure fraction
was added to the first fraction yielding 787 mg (91%) of the title
compound. NMR (400 MHz, CDCl.sub.3) 0.78 (t, 6H), 0.92 1.12 (m,
4H), 1.12 1.46 (m, 6H), 1.54 (s, 9H), 1.58 1.72 (m, 2H:), 2.14 (s,
3H), 3.8 4.05 (m, 2H), 4.32 (brs, NH), 4.56 (ABq, 2H), 5.56 (d,
1H), 6.56 (s, 1H), 7.04 (t, 1H), 7.10 (brd, 2H) 7.24 7.42 (m, 8H),
7.84 (d, NH); m/z 694.7 (M-H).sup.-.
Method 3
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetra-
hydro-1,2,5-benzothiadiazepine
To a solution of
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyl-methoxy-2,3,-
4,5-tetrahydro-1,2,5-benzothiadiazepine (Method 4; 0.024 g,
4.49*10.sup.-5 mol) in EtOH (3 ml) was added NaOH (0.007 g,
1.80*10.sup.-4 mol) and the mixture was stirred over night The
solvent was removed under reduced pressure and the residue was
purified by preparative HPLC using an MeCN/ammonium acetate buffer
as eluent and freeze-dried The title compound was obtained in 0.021
g (92%) as a white solid. NMR (400 MHz, CD.sub.3OD) 0.70 0.85 (m,
6H), 1.00 1.70 (m, 12H), 2.10 (s, 3H), 3.90 (brs, 2H), 4.55 (s,
2H), 6.60 (s, 1H), 6.90 7.35 (m, 6H).
Method 4
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,-
5-tetrahydro-1,2,5-benzothiadiazepine
To a suspension of
1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-
-benzothiadiazepine (prepared according to WO 98/38182; 0.218 g,
5.65*10.sup.-4 mol) in DMF (5 ml) was added NaSMe (0.210 g, 2.83
mmol, 95%), and the mixture was stirred for 5 hours at 120.degree.
C. The solvent was removed under reduced pressure and the residue
was partitioned between EtOAc and 0.5 M HCl. The aqueous layer was
extracted twice more with EtOAc and the combined organic extracts
were dried (MgSO.sub.4) and concentrated The residue was dissolved
in MeCN (7 ml) and ethyl bromoacetate (0.063 ml, 5.65*10.sup.-4
mol), tetrabutylammonium bromide (0.018 g, 5.65*10.sup.-5 mol) and
sodium carbonate (0.250 g, 2.36 mmol) were added. The mixture was
stirred over night at 80.degree. C. The solvent was removed under
reduced pressure and the residue was partitioned between EtOAc and
0.5 M HCl. The organic layer was washed with brine, dried
(MgSO.sub.4) and concentrated Flash chromatography on silica gel
(Hex:EtOAc-6:1) gave the title compound as a colourless oil 0.024 g
(8%). NMR (400 MHz, CDCl.sub.3) 0.70 0.85 (m, 6H), 0.90 1.70 (m,
15H), 2.10 (s, 3H), 3.90 (bs, 2H), 4,20 (bs, 1H), 4.25 (q, 2H),
4.65 (s, 2H), 6.55 (s, 1H), 6.95 7.35 (m, 6H).
Method 5
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-.alpha.-carboxy-4-hy-
droxybenzyl)
carbamoylmethoxy]-2,3,4,5tetrahydro-1,2,5-benzothiadiazepine
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetr-
ahydro-1,2,5-benzothiadiazepine (Method 3; 295 mg, 0.58 mmol) was
dissolved in 10 ml DCM.
4-(1-(R)-t-Butoxycarbonyl-1-aminomethyl)phenol (Method 6; 160 mg,
0.72 mmol), 2,6-lutidine (140 .mu.l, 1.20 mmol) and TBTU (230 mg,
0.72 mmol) were added successively. The mixture was stirred for 3
h. Additional 4-(1-(R)-t-butoxycarbonyl-1-aminomethyl)phenol
(Method 6; 10 mg, 0.04 mmol) was added and stirring was continued
for 2 h. DCM (20 ml) was added and the solution was washed with 5%
NaHCO.sub.3 (20 ml), 0.3M KHSO.sub.4 (20 ml), brine (20 ml) before
it was dried and concentrated to a volume of 10 ml. The tert-butyl
ester of the title compound was confirmed; m/z: 729
(M+18(NH.sub.4.sup.+)). TFA (1.3 ml) was added and the mixture was
stirred for 4.5 h and concentrated. The crude product was purified
by preparative HPLC using a C8 column (5.times.500 mm) and a
gradient (40/60 to 70/30 over 40 min) of MeCN/0.1M ammonium acetate
buffer as eluent. Lyophilization yielded the title compound in
77.5% (302 mg). NMR (400 MHz): 0.8 (t, 6H), 1.0 1.2 (m, 6H), 1.25
1.4 (m, 2H) 1.4 1;5 (m, 2H), 1.55 1.7 (m, 2H), 2.1 (s, 3H), 3.95
(brs, 2H), 4.6 (ABq, 2H), 5.3 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H),
7.05 (t, 1H) 7.15 7.4 (m, 7H); m/z: 673 (M+18
(NH.sub.4.sup.+)).
Method 6
4-(1-(R)-t-Butoxycarbonyl-1-aminomethyl)phenol
Sulfuric acid (1 ml conc.) was added to a solution of
D-(R)-4-hydroxyphenylglycine (1.0 g, 6.0 mmol) in 1,4dioxane (8 ml)
placed in a Teflon.RTM. flask The flask was cooled to -78.degree.
C. and isobutylene (8 g, 142.6 mmol, condensed at -78.degree. C.)
was added. The flask was placed in an autoclave at room temperature
and stirred for 15 h. The autoclave was cooled on ice before
opened. The excess isobutylene was allowed to evaporate and the
remaining solution was poured into aqueous NaOH (2M, 20 ml) and was
extracted with diethyl ether to remove formed by-product. The
aqueous phase was slightly acidified to attain pH=10 using 2M HCl
and was extracted with diethyl ether (3.times.75 ml). The organic
phase was washed with brine, dried and concentrated. The obtained
product was recrystallized in diethyl etherhexane. Mass: 0.55 g
(41%). NMR (600 MHz, CDCl.sub.3): 1.45 (s, 9H), 4.45 (s, 1H), 6.8
(d, 2H), 7.25 (d, 2H); m/z: 224.
* * * * *